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Miyara S, Adler M, Umansky KB, Häußler D, Bassat E, Divinsky Y, Elkahal J, Kain D, Lendengolts D, Ramirez Flores RO, Bueno-Levy H, Golani O, Shalit T, Gershovits M, Weizman E, Genzelinakh A, Kimchi DM, Shakked A, Zhang L, Wang J, Baehr A, Petrover Z, Sarig R, Dorn T, Moretti A, Saez-Rodriguez J, Kupatt C, Tanaka EM, Medzhitov R, Krüger A, Mayo A, Alon U, Tzahor E. Cold and hot fibrosis define clinically distinct cardiac pathologies. Cell Syst 2025:101198. [PMID: 39970910 DOI: 10.1016/j.cels.2025.101198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 09/28/2024] [Accepted: 01/27/2025] [Indexed: 02/21/2025]
Abstract
Fibrosis remains a major unmet medical need. Simplifying principles are needed to better understand fibrosis and to yield new therapeutic approaches. Fibrosis is driven by myofibroblasts that interact with macrophages. A mathematical cell-circuit model predicts two types of fibrosis: hot fibrosis driven by macrophages and myofibroblasts and cold fibrosis driven by myofibroblasts alone. Testing these concepts in cardiac fibrosis resulting from myocardial infarction (MI) and heart failure (HF), we revealed that acute MI leads to cold fibrosis whereas chronic injury (HF) leads to hot fibrosis. MI-driven cold fibrosis is conserved in pigs and humans. We computationally identified a vulnerability of cold fibrosis: the myofibroblast autocrine growth factor loop. Inhibiting this loop by targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-MI in mice. Our study demonstrates the utility of the concepts of hot and cold fibrosis and the feasibility of a circuit-to-target approach to pinpoint a treatment strategy that reduces fibrosis. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Shoval Miyara
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Miri Adler
- Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT, USA
| | - Kfir B Umansky
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Daniel Häußler
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, Munich, Germany
| | - Elad Bassat
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
| | - Yalin Divinsky
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Jacob Elkahal
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - David Kain
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Daria Lendengolts
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ricardo O Ramirez Flores
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany
| | - Hanna Bueno-Levy
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ofra Golani
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Tali Shalit
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Michael Gershovits
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Eviatar Weizman
- The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Alexander Genzelinakh
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Danielle M Kimchi
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Avraham Shakked
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Lingling Zhang
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Jingkui Wang
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
| | - Andrea Baehr
- Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Zachary Petrover
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Rachel Sarig
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Tatjana Dorn
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany
| | - Alessandra Moretti
- DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany
| | - Julio Saez-Rodriguez
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, UK
| | - Christian Kupatt
- Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Elly M Tanaka
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
| | - Ruslan Medzhitov
- Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT, USA; Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, Yale, New Haven, CT, USA
| | - Achim Krüger
- TUM School of Medicine and Health, Institute of Experimental Oncology and Therapy Research, Technical University of Munich, Munich, Germany
| | - Avi Mayo
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Uri Alon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
| | - Eldad Tzahor
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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2
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Zhang X, Tian H, Xie C, Yang Y, Li P, Cheng J. The role and mechanism of vascular wall cell ion channels in vascular fibrosis remodeling. Channels (Austin) 2024; 18:2418128. [PMID: 39425532 PMCID: PMC11492694 DOI: 10.1080/19336950.2024.2418128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 09/24/2024] [Accepted: 10/12/2024] [Indexed: 10/21/2024] Open
Abstract
Fibrosis is usually the final pathological state of many chronic inflammatory diseases and may lead to organ malfunction. Excessive deposition of extracellular matrix (ECM) molecules is a characteristic of most fibrotic tissues. The blood vessel wall contains three layers of membrane structure, including the intima, which is composed of endothelial cells; the media, which is composed of smooth muscle cells; and the adventitia, which is formed by the interaction of connective tissue and fibroblasts. The occurrence and progression of vascular remodeling are closely associated with cardiovascular diseases, and vascular remodeling can alter the original structure and function of the blood vessel. Dysregulation of the composition of the extracellular matrix in blood vessels leads to the continuous advancement of vascular stiffening and fibrosis. Vascular fibrosis reaction leads to excessive deposition of the extracellular matrix in the vascular adventitia, reduces vessel compliance, and ultimately alters key aspects of vascular biomechanics. The pathogenesis of fibrosis in the vasculature and strategies for its reversal have become interesting and important challenges. Ion channels are widely expressed in the cardiovascular system; they regulate blood pressure, maintain cardiovascular function homeostasis, and play important roles in ion transport, cell differentiation, proliferation. In blood vessels, different types of ion channels in fibroblasts, smooth muscle cells and endothelial cells may be relevant mediators of the development of fibrosis in organs or tissues. This review discusses the known roles of ion channels in vascular fibrosis remodeling and discusses potential therapeutic targets for regulating remodeling and repair after vascular injury.
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Affiliation(s)
- Xiaolin Zhang
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Hai Tian
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Cheng Xie
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Yan Yang
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Pengyun Li
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
| | - Jun Cheng
- Key Lab of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Public Center of Experimental Technology, Hemodynamics and Medical Engineering Combination Key Laboratory of Luzhou, Southwest Medical University, Luzhou, China
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3
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Wu D, Li S, Chen M, Zhang S, Wang Q. C1q/tumor necrosis factor-related protein-6 suppresses the angiotensin II-induced differentiation of cardiac fibroblasts to myofibroblasts via activation of the AMPK pathway. Tissue Cell 2024; 91:102627. [PMID: 39581070 DOI: 10.1016/j.tice.2024.102627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
C1q/tumor necrosis factor-related protein-6 (CTRP6) has multiple protective effects against cardiovascular diseases. Myofibroblast differentiation plays a critical role in cardiac fibrosis under various cardiac pathological conditions. The aim of the present study was to determine the effects of CTRP6 on cardiac fibrosis, and to identify the possible mechanisms of action. Toward this end, we measured the expression of fibrotic markers, including collagen I, collagen III, CTGF, and TGFβ1, and assessed the effects of CTRP6 on cardiac fibroblast differentiation into myofibroblasts. CTRP6 inhibited the expression of the angiotensin II (Ang II)-induced myofibroblast markers α-SMA and SM22, and of profibrotic molecules, including collagen I, collagen III, CTGF, TGFβ1, MMP2, MMP9, and TIMP1. Furthermore, CTRP6 significantly attenuated the proliferation and migration of cardiac fibroblasts incubated with Ang II and activated the phosphorylation of AMP-activated protein kinase (AMPK). Incubation with an AMPK inhibitor reversed the subsequent inhibitory effects of CTRP6 on Ang II-induced myofibroblast differentiation. Therefore, CTRP6 suppresses cardiac fibrosis by inhibition of myofibroblast differentiation via AMPK pathway activation, suggesting CTRP6 as a target for the treatment of cardiac fibrosis.
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Affiliation(s)
- Dan Wu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
| | - Shuyu Li
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
| | - Meng Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China
| | - Shujing Zhang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China
| | - Qian Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China
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4
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Liu Z. Gene expression profile of human placental villous pericytes in the first trimester - An analysis by single-cell RNA sequencing. Reprod Biol 2024; 24:100919. [PMID: 38941941 DOI: 10.1016/j.repbio.2024.100919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/30/2024]
Abstract
Mesenchymal cells within theplacental villi play a crucial role in shaping the morphology of branching structures and driving the development of blood vessels. However, the markers and functions of placental villous pericytes (PVPs) as distinct subgroups of placental villous mesenchymal cells, remain unclear. Therefore, in this study, the markers and functions of PVPs were investigated. Single-cell sequencing data from the first-trimester placental villi was obtained and the Seurat tool was used to identify PVP markers. Gene Ontology (GO) analysis of specific genes was performed using the DAVID database. The Cellchat tool was employed to investigate the interaction signals between the PVPs and other cells. Expression of the PVP markers was confirmed using immunofluorescence. Presence of extracellular vesicles in the placental villous mesenchyme and PVPs was examined by transmission electron microscopy. Our findings revealed that renin (REN) and amphiregulin (AREG)-positive fibroblasts in the placental villi specifically expressed several classic pericyte markers. In the first trimester, certain conserved functions of pericytes were observed and they displayed tissue-specific functions such as in the integrin-mediated signaling pathway and extracellular exosomes. Moreover, the placental villous mesenchyme was found to be rich in extracellular vesicles. AREG is specifically transcribed in the first trimester PVPs, however, its protein was located in syncytiotrophoblasts. These insights contribute to a comprehensive understanding of early placental development and offer new therapeutic targets for placenta-derived pregnancy complications.
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Affiliation(s)
- Zhao Liu
- Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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5
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Wei Q, Gan C, Sun M, Xie Y, Liu H, Xue T, Deng C, Mo C, Ye T. BRD4: an effective target for organ fibrosis. Biomark Res 2024; 12:92. [PMID: 39215370 PMCID: PMC11365212 DOI: 10.1186/s40364-024-00641-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Fibrosis is an excessive wound-healing response induced by repeated or chronic external stimuli to tissues, significantly impacting quality of life and primarily contributing to organ failure. Organ fibrosis is reported to cause 45% of all-cause mortality worldwide. Despite extensive efforts to develop new antifibrotic drugs, drug discovery has not kept pace with the clinical demand. Currently, only pirfenidone and nintedanib are approved by the FDA to treat pulmonary fibrotic illness, whereas there are currently no available antifibrotic drugs for hepatic, cardiac or renal fibrosis. The development of fibrosis is closely related to epigenetic alterations. The field of epigenetics primarily studies biological processes, including chromatin modifications, epigenetic readers, DNA transcription and RNA translation. The bromodomain and extra-terminal structural domain (BET) family, a class of epigenetic readers, specifically recognizes acetylated histone lysine residues and promotes the formation of transcriptional complexes. Bromodomain-containing protein 4 (BRD4) is one of the most well-researched proteins in the BET family. BRD4 is implicated in the expression of genes related to inflammation and pro-fibrosis during fibrosis. Inhibition of BRD4 has shown promising anti-fibrotic effects in preclinical studies; however, no BRD4 inhibitor has been approved for clinical use. This review introduces the structure and function of BET proteins, the research progress on BRD4 in organ fibrosis, and the inhibitors of BRD4 utilized in fibrosis. We emphasize the feasibility of targeting BRD4 as an anti-fibrotic strategy and discuss the therapeutic potential and challenges associated with BRD4 inhibitors in treating fibrotic diseases.
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Affiliation(s)
- Qun Wei
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Cailing Gan
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Meng Sun
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuting Xie
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hongyao Liu
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Taixiong Xue
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Conghui Deng
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunheng Mo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Tinghong Ye
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Ningxia Medical University, Yin Chuan, 640100, China.
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6
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Lazaropoulos MP, Gibb AA, Chapski DJ, Nair AA, Reiter AN, Roy R, Eaton DM, Bedi KC, Margulies KB, Wellen KE, Estarás C, Vondriska TM, Elrod JW. Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program. NATURE CARDIOVASCULAR RESEARCH 2024; 3:869-882. [PMID: 39196175 PMCID: PMC11358007 DOI: 10.1038/s44161-024-00502-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 05/31/2024] [Indexed: 08/29/2024]
Abstract
Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.
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Affiliation(s)
- Michael P Lazaropoulos
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Andrew A Gibb
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Douglas J Chapski
- Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Abheya A Nair
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Allison N Reiter
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Rajika Roy
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Deborah M Eaton
- Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kenneth C Bedi
- Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kenneth B Margulies
- Cardiovascular Institute and Cardiovascular Medicine Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kathryn E Wellen
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Conchi Estarás
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Thomas M Vondriska
- Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Departments Medicine/Cardiology and Physiology, and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - John W Elrod
- Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
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Tu J, Chen X, Li C, Liu C, Huang Y, Wang X, Liang H, Yuan X. Nintedanib Mitigates Radiation-Induced Pulmonary Fibrosis by Suppressing Epithelial Cell Inflammatory Response and Inhibiting Fibroblast-to-Myofibroblast Transition. Int J Biol Sci 2024; 20:3353-3371. [PMID: 38993568 PMCID: PMC11234214 DOI: 10.7150/ijbs.92620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 05/28/2024] [Indexed: 07/13/2024] Open
Abstract
Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.
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Affiliation(s)
- Jingyao Tu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinyi Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunya Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaofan Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongbiao Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hang Liang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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8
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Völkers M, Preiss T, Hentze MW. RNA-binding proteins in cardiovascular biology and disease: the beat goes on. Nat Rev Cardiol 2024; 21:361-378. [PMID: 38163813 DOI: 10.1038/s41569-023-00958-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
Cardiac development and function are becoming increasingly well understood from different angles, including signalling, transcriptional and epigenetic mechanisms. By contrast, the importance of the post-transcriptional landscape of cardiac biology largely remains to be uncovered, building on the foundation of a few existing paradigms. The discovery during the past decade of hundreds of additional RNA-binding proteins in mammalian cells and organs, including the heart, is expected to accelerate progress and has raised intriguing possibilities for better understanding the intricacies of cardiac development, metabolism and adaptive alterations. In this Review, we discuss the progress and new concepts on RNA-binding proteins and RNA biology and appraise them in the context of common cardiovascular clinical conditions, from cell and organ-wide perspectives. We also discuss how a better understanding of cardiac RNA-binding proteins can fill crucial knowledge gaps in cardiology and might pave the way to developing better treatments to reduce cardiovascular morbidity and mortality.
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Affiliation(s)
- Mirko Völkers
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg and Mannheim, Germany
| | - Thomas Preiss
- Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
- Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - Matthias W Hentze
- European Molecular Biology Laboratory, Heidelberg, Germany.
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.
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9
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Acharya P, Parkins S, Tranter M. RNA binding proteins as mediators of pathological cardiac remodeling. Front Cell Dev Biol 2024; 12:1368097. [PMID: 38818408 PMCID: PMC11137256 DOI: 10.3389/fcell.2024.1368097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 05/01/2024] [Indexed: 06/01/2024] Open
Abstract
RNA binding proteins (RBPs) play a central in the post-transcriptional regulation of gene expression, which can account for up to 50% of all variations in protein expression within a cell. Following their binding to target RNAs, RBPs most typically confer changes in gene expression through modulation of alternative spicing, RNA stabilization/degradation, or ribosome loading/translation rate. All of these post-transcriptional regulatory processes have been shown to play a functional role in pathological cardiac remodeling, and a growing body of evidence is beginning to identify the mechanistic contribution of individual RBPs and their cardiac RNA targets. This review highlights the mechanisms of RBP-dependent post-transcriptional gene regulation in cardiomyocytes and fibroblasts and our current understanding of how RNA binding proteins functionally contribute to pathological cardiac remodeling.
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Affiliation(s)
- Pooja Acharya
- Department of Molecular Medicine and Therapeutics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Sharon Parkins
- Department of Molecular Medicine and Therapeutics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Michael Tranter
- Department of Molecular Medicine and Therapeutics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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10
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Ren FF, Zhao L, Jiang XY, Zhang JJ, Gou JM, Yu XY, Wu SJ, Li L. Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway. Acta Pharmacol Sin 2024; 45:312-326. [PMID: 37833535 PMCID: PMC10789762 DOI: 10.1038/s41401-023-01168-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/13/2023] [Indexed: 10/15/2023] Open
Abstract
Apoptosis plays a critical role in the development of heart failure, and sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid naturally occurring in blood plasma. Some studies have shown that SPC inhibits hypoxia-induced apoptosis in myofibroblasts, the crucial non-muscle cells in the heart. Calmodulin (CaM) is a known SPC receptor. In this study we investigated the role of CaM in cardiomyocyte apoptosis in heart failure and the associated signaling pathways. Pressure overload was induced in mice by trans-aortic constriction (TAC) surgery. TAC mice were administered SPC (10 μM·kg-1·d-1) for 4 weeks post-surgery. We showed that SPC administration significantly improved survival rate and cardiac hypertrophy, and inhibited cardiac fibrosis in TAC mice. In neonatal mouse cardiomyocytes, treatment with SPC (10 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, fibroblast-to-myofibroblast transition and cell apoptosis accompanied by reduced Bax and phosphorylation levels of CaM, JNK and p38, as well as upregulated Bcl-2, a cardiomyocyte-protective protein. Thapsigargin (TG) could enhance CaM functions by increasing Ca2+ levels in cytoplasm. TG (3 μM) annulled the protective effect of SPC against Ang II-induced cardiomyocyte apoptosis. Furthermore, we demonstrated that SPC-mediated inhibition of cardiomyocyte apoptosis involved the regulation of p38 and JNK phosphorylation, which was downstream of CaM. These results offer new evidence for SPC regulation of cardiomyocyte apoptosis, potentially providing a new therapeutic target for cardiac remodeling following stress overload.
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Affiliation(s)
- Fang-Fang Ren
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lin Zhao
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xian-Yun Jiang
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jing-Jing Zhang
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jia-Min Gou
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiao-Yu Yu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Shu-Jin Wu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lei Li
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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11
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Hung CC, Chen KH, Hsu HH, Chang MY, Ko YC, Yang HY, Yang CW. Noscapine alleviates unilateral ureteral obstruction-induced inflammation and fibrosis by regulating the TGFβ1/Smads signaling pathways. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119594. [PMID: 37730129 DOI: 10.1016/j.bbamcr.2023.119594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 09/02/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023]
Abstract
Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.
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Affiliation(s)
- Cheng-Chieh Hung
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
| | - Kuan-Hsing Chen
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Hsiang-Hao Hsu
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Ming-Yang Chang
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Yi-Ching Ko
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Huang-Yu Yang
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Chih-Wei Yang
- Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan
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12
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Abdelnaby AE, Trebak M. Store-Operated Ca 2+ Entry in Fibrosis and Tissue Remodeling. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2024; 7:25152564241291374. [PMID: 39659877 PMCID: PMC11629433 DOI: 10.1177/25152564241291374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 08/29/2024] [Accepted: 09/27/2024] [Indexed: 12/12/2024]
Abstract
Fibrosis is a pathological condition characterized by excessive tissue deposition of extracellular matrix (ECM) components, leading to scarring and impaired function across multiple organ systems. This complex process is mediated by a dynamic interplay between cell types, including myofibroblasts, fibroblasts, immune cells, epithelial cells, and endothelial cells, each contributing distinctively through various signaling pathways. Critical to the regulatory mechanisms involved in fibrosis is store-operated calcium entry (SOCE), a calcium entry pathway into the cytosol active at the endoplasmic reticulum-plasma membrane contact sites and common to all cells. This review addresses the multifactorial nature of fibrosis with a focus on the pivotal roles of different cell types. We highlight the essential functions of myofibroblasts in ECM production, the transformation of fibroblasts, and the participation of immune cells in modulating the fibrotic landscape. We emphasize the contributions of SOCE in these different cell types to fibrosis, by exploring the involvement of SOCE in cellular functions such as proliferation, migration, secretion, and inflammatory responses. The examination of the cellular and molecular mechanisms of fibrosis and the role of SOCE in these mechanisms offers the potential of targeting SOCE as a therapeutic strategy for mitigating or reversing fibrosis.
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Affiliation(s)
- Ahmed Emam Abdelnaby
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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13
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Liang G, Oh TG, Hah N, Tiriac H, Shi Y, Truitt ML, Antal CE, Atkins AR, Li Y, Fraser C, Ng S, Pinto AFM, Nelson DC, Estepa G, Bashi S, Banayo E, Dai Y, Liddle C, Yu RT, Hunter T, Engle DD, Han H, Von Hoff DD, Downes M, Evans RM. Inhibiting stromal Class I HDACs curbs pancreatic cancer progression. Nat Commun 2023; 14:7791. [PMID: 38057326 PMCID: PMC10700526 DOI: 10.1038/s41467-023-42178-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 09/27/2023] [Indexed: 12/08/2023] Open
Abstract
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
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Affiliation(s)
- Gaoyang Liang
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Tae Gyu Oh
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Department of Oncology Science, OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA
| | - Nasun Hah
- Next Generation Sequencing Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Hervé Tiriac
- Department of Surgery, University of California San Diego, La Jolla, CA, 92093, USA
| | - Yu Shi
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Bristol Myer Squibb, 10300 Campus Point Drive, Suite 100, San Diego, CA, 92121, USA
| | - Morgan L Truitt
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Corina E Antal
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA
| | - Annette R Atkins
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Yuwenbin Li
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Cory Fraser
- HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center, Scottsdale, AZ, 85260, USA
| | - Serina Ng
- Molecular Medicine Division, The Translational Genomic Research Institute, Phoenix, AZ, 85004, USA
| | - Antonio F M Pinto
- Mass Spectrometry Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Dylan C Nelson
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Gabriela Estepa
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Senada Bashi
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Ester Banayo
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Yang Dai
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Ruth T Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Tony Hunter
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Dannielle D Engle
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Haiyong Han
- Molecular Medicine Division, The Translational Genomic Research Institute, Phoenix, AZ, 85004, USA
| | - Daniel D Von Hoff
- HonorHealth Scottsdale Osborn Medical Center and Shea Medical Center, Scottsdale, AZ, 85260, USA
- Molecular Medicine Division, The Translational Genomic Research Institute, Phoenix, AZ, 85004, USA
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
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14
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Wang AH, Ma HY, Yi YL, Zhu SJ, Yu ZW, Zhu J, Mei S, Bahetibike S, Lu YQ, Huang LT, Yang RY, Rui-Wang, Xiao SL, Qi R. Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-β/Smads pathway. Eur J Pharmacol 2023; 960:176116. [PMID: 38059443 DOI: 10.1016/j.ejphar.2023.176116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 12/08/2023]
Abstract
Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-β/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-β/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-β/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-β/Smads signaling pathway.
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Affiliation(s)
- An-Hui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Hao-Yue Ma
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Yan-Liang Yi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Su-Jie Zhu
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Zhe-Wei Yu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Jie Zhu
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Si Mei
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Shamuha Bahetibike
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - You-Qun Lu
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Li-Ting Huang
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Ruo-Yao Yang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Rui-Wang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China
| | - Su-Long Xiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
| | - Rong Qi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
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15
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Ioakeimidis NS, Pitsis A, Zegkos T, Ntelios D, Kelpis T, Papamitsou T, Parcharidou D, Gossios T, Efthimiadis G, Meditskou S. Periostin is overexpressed, correlated with fibrosis and differs among grades of cardiomyocyte hypertrophy in myectomy tissue of patients with hypertrophic cardiomyopathy. PLoS One 2023; 18:e0293427. [PMID: 37939043 PMCID: PMC10631645 DOI: 10.1371/journal.pone.0293427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Periostin, a secreted matricellular protein, has been implicated in cardiac extracellular matrix remodeling and fibrosis. Evidence suggest that periostin stimulates cardiomyocyte hypertrophy. The current study aims to investigate the extent of periostin expression in patients with advanced Hypertrophic Cardiomyopathy (HCM) and its correlation with fibrosis and hallmark histopathological features of the disease. Interventricular septal tissue from thirty-nine HCM patients who underwent myectomy and five controls who died from non-cardiac causes was obtained. Staining with Masson's Trichrome and immunohistochemistry were used to localize fibrosis and periostin respectively. The extent of fibrosis and the expression of periostin were defined as the stained percentage of total tissue area using digital pathology software. Periostin expression was higher in HCM patients compared to controls (p<0.0001), positively correlated with the extent of fibrosis (r = 0.82, p<0.001), positively correlated with maximal interventricular septal thickness (Rho = 0.33, p = 0.04) and negatively correlated with LVEF (r = -0.416, p = 0.009). Periostin was approximately co-localized with fibrosis. Mean periostin expression was lower in patients with mild grade cardiomyocyte hypertrophy compared to those with moderate grade (p = 0.049) and lower in patients with mild grade replacement fibrosis compared to moderate grade (p = 0.036). In conclusion, periostin is overexpressed in advanced HCM, correlated with fibrosis and possibly related to cardiomyocyte hypertrophy.
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Affiliation(s)
- Nikolaos S. Ioakeimidis
- Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonios Pitsis
- Department of Cardiac Surgery, European Interbalkan Medical Center, Thessaloniki, Greece
| | - Thomas Zegkos
- First Department of Cardiology, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Ntelios
- First Department of Cardiology, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece
| | - Timotheos Kelpis
- Department of Cardiac Surgery, European Interbalkan Medical Center, Thessaloniki, Greece
| | - Theodora Papamitsou
- Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Despoina Parcharidou
- First Department of Cardiology, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece
| | - Thomas Gossios
- First Department of Cardiology, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece
| | - Georgios Efthimiadis
- First Department of Cardiology, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece
| | - Soultana Meditskou
- Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
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16
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Liang G, Oh TG, Hah N, Tiriac H, Shi Y, Truitt ML, Antal CE, Atkins AR, Li Y, Fraser C, Ng S, Pinto AFM, Nelson DC, Estepa G, Bashi S, Banayo E, Dai Y, Liddle C, Yu RT, Hunter T, Engle DD, Han H, Von Hoff DD, Downes M, Evans RM. Inhibiting Stromal Class I HDACs Curbs Pancreatic Cancer Progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.12.557260. [PMID: 37745372 PMCID: PMC10515810 DOI: 10.1101/2023.09.12.557260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
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17
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Ishikane S, Arioka M, Takahashi-Yanaga F. Promising small molecule anti-fibrotic agents: Newly developed or repositioned drugs targeting myofibroblast transdifferentiation. Biochem Pharmacol 2023; 214:115663. [PMID: 37336252 DOI: 10.1016/j.bcp.2023.115663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/11/2023] [Accepted: 06/13/2023] [Indexed: 06/21/2023]
Abstract
Fibrosis occurs in all organs and tissues except the brain, and its progression leads to dysfunction of affected organs. Fibrosis-induced organ dysfunction results from the loss of elasticity, strength, and functionality of tissues due to the extracellular matrix secreted by myofibroblasts that express smooth muscle-type actin as a marker. Myofibroblasts, which play a major role in fibrosis, were once thought to originate exclusively from activated fibroblasts; however, it is now clear that myofibroblasts are diverse in origin, from epithelial cells, endothelial cells, adipocytes, macrophages, and other cells. Fibrosis of vital organs, such as the heart, lungs, kidneys, and liver, is a serious chronic disease that ultimately leads to death. Currently, anti-cancer drugs have made remarkable progress, as evidenced by the development of many molecular-targeted drugs, and are making a significant contribution to improving the prognosis of cancer treatment. However, the development of anti-fibrotic agents, which also play an important role in prognosis, has lagged. In this review, the current knowledge regarding myofibroblasts is summarized, with particular attention given to their origin and transdifferentiation signaling pathways (e.g., TGF-β, Wnt/β-catenin, YAP/TAZ and AMPK signaling pathways). The development of new small molecule anti-fibrotic agents and the repositioning of existing drugs targeting myofibroblast transdifferentiation are discussed.
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Affiliation(s)
- Shin Ishikane
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Masaki Arioka
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan
| | - Fumi Takahashi-Yanaga
- Department of Pharmacology, Faculty of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
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18
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Zhao Q, Shao T, Zhu Y, Zong G, Zhang J, Tang S, Lin Y, Ma H, Jiang Z, Xu Y, Wu X, Zhang T. An MRTF-A-ZEB1-IRF9 axis contributes to fibroblast-myofibroblast transition and renal fibrosis. Exp Mol Med 2023:10.1038/s12276-023-00990-6. [PMID: 37121967 DOI: 10.1038/s12276-023-00990-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/23/2023] [Accepted: 02/14/2023] [Indexed: 05/02/2023] Open
Abstract
Myofibroblasts, characterized by the expression of the matricellular protein periostin (Postn), mediate the profibrogenic response during tissue repair and remodeling. Previous studies have demonstrated that systemic deficiency in myocardin-related transcription factor A (MRTF-A) attenuates renal fibrosis in mice. In the present study, we investigated the myofibroblast-specific role of MRTF-A in renal fibrosis and the underlying mechanism. We report that myofibroblast-specific deletion of MRTF-A, achieved through crossbreeding Mrtfa-flox mice with Postn-CreERT2 mice, led to amelioration of renal fibrosis. RNA-seq identified zinc finger E-Box binding homeobox 1 (Zeb1) as a downstream target of MRTF-A in renal fibroblasts. MRTF-A interacts with TEA domain transcription factor 1 (TEAD1) to bind to the Zeb1 promoter and activate Zeb1 transcription. Zeb1 knockdown retarded the fibroblast-myofibroblast transition (FMyT) in vitro and dampened renal fibrosis in mice. Transcriptomic assays showed that Zeb1 might contribute to FMyT by repressing the transcription of interferon regulatory factor 9 (IRF9). IRF9 knockdown overcame the effect of Zeb1 depletion and promoted FMyT, whereas IRF9 overexpression antagonized TGF-β-induced FMyT. In conclusion, our data unveil a novel MRTF-A-Zeb1-IRF9 axis that can potentially contribute to fibroblast-myofibroblast transition and renal fibrosis. Screening for small-molecule compounds that target this axis may yield therapeutic options for the mollification of renal fibrosis.
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Affiliation(s)
- Qianwen Zhao
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Tinghui Shao
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yuwen Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Gengjie Zong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Junjie Zhang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Shifan Tang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yanshan Lin
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Hongzhen Ma
- Department of Geriatric Nephrology, First Affiliated Hospital to Nanjing Medical University, Nanjing, China
| | - Zhifan Jiang
- Department of Geriatric Nephrology, First Affiliated Hospital to Nanjing Medical University, Nanjing, China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xiaoyan Wu
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China.
| | - Tao Zhang
- Department of Geriatric Nephrology, First Affiliated Hospital to Nanjing Medical University, Nanjing, China.
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19
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Diao HY, Zhu W, Liu J, Yin S, Wang JH, Li CL. Salvianolic Acid A Improves Rat Kidney Injury by Regulating MAPKs and TGF-β1/Smads Signaling Pathways. Molecules 2023; 28:3630. [PMID: 37110864 PMCID: PMC10144349 DOI: 10.3390/molecules28083630] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Salvianolic acid A (SAA) is one of the major components in Salvia miltiorrhiza Bge., with various pharmacological activities, and is likely to be a promising agent for the treatment of kidney diseases. The purpose of this study was to explore the protective effect and mechanisms of SAA on kidney disease. In this study, the improvement effects of SAA (10, 20, 40 mg/kg, i.g.) on kidney injury rats were investigated by detecting the levels of KIM-1, NGAL in serum and UP in the urine of AKI model rats established with gentamicin, as well as the levels of SCr and UREA in serum and IL-6, IL-12, MDA and T-SOD in the kidneys of CKD model rats established with 5/6 nephrectomy. HE and Masson staining were used to observe the histopathological changes in the kidney. Network pharmacology and Western blotting were used to explore the mechanism of SAA in improving kidney injury. The results showed that SAA improved kidney function in kidney injury rats by reducing the kidney index and pathological injury by HE and Masson staining, reducing the levels of KIM-1, NGAL and UP in AKI rats and UREA, SCr and UP in CKD rats, as well as exerting anti-inflammatory and anti-oxidative stress effects by inhibiting the release of IL-6 and IL-12, reducing MDA and increasing T-SOD. Western blotting results showed that SAA significantly reduced the phosphorylation levels of ERK1/2, p38, JNK and smad2/3, and the expression of TLR-4 and smad7. In conclusion, SAA plays a significant role in improving kidney injury in rats and the mechanism may be achieved by regulating the MAPKs and TGF-β1/smads signaling pathways.
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Affiliation(s)
- Hai-Yang Diao
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Wei Zhu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jie Liu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Sheng Yin
- Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jin-Hui Wang
- Department of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Chun-Li Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China
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20
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Nelson AR, Bugg D, Davis J, Saucerman JJ. Network model integrated with multi-omic data predicts MBNL1 signals that drive myofibroblast activation. iScience 2023; 26:106502. [PMID: 37091233 PMCID: PMC10119756 DOI: 10.1016/j.isci.2023.106502] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 01/09/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
RNA-binding protein muscleblind-like1 (MBNL1) was recently identified as a central regulator of cardiac wound healing and myofibroblast activation. To identify putative MBNL1 targets, we integrated multiple genome-wide screens with a fibroblast network model. We expanded the model to include putative MBNL1-target interactions and recapitulated published experimental results to validate new signaling modules. We prioritized 14 MBNL1 targets and developed novel fibroblast signaling modules for p38 MAPK, Hippo, Runx1, and Sox9 pathways. We experimentally validated MBNL1 regulation of p38 expression in mouse cardiac fibroblasts. Using the expanded fibroblast model, we predicted a hierarchy of MBNL1 regulated pathways with strong influence on αSMA expression. This study lays a foundation to explore the network mechanisms of MBNL1 signaling central to fibrosis.
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Affiliation(s)
- Anders R. Nelson
- Department of Pharmacology, University of Virginia, 1340 Jefferson Park Avenue, Pinn Hall, 5th Floor, PO Box 800735, Charlottesville, VA 22908-0735, USA
| | - Darrian Bugg
- Department of Lab Medicine & Pathology, University of Washington, 1959 NE Pacific Street Box 357470, Seattle, WA 98195, USA
| | - Jennifer Davis
- Department of Lab Medicine & Pathology, University of Washington, 1959 NE Pacific Street Box 357470, Seattle, WA 98195, USA
- Department of Bioengineering, University of Washington, PO Box 355061, Seattle, WA 98195-5061, USA
- Institute for Stem Cell & Regenerative Medicine, University of Washington, 850 Republican Street, PO Box 358056, Seattle, WA 98109, USA
| | - Jeffrey J. Saucerman
- Department of Biomedical Engineering, University of Virginia, PO Box 800759, Charlottesville, VA 22903 , USA
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21
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Kodama Y, Masuda S, Ohmori T, Kanamaru A, Tanaka M, Sakaguchi T, Nakagawa M. Response to Mechanical Properties and Physiological Challenges of Fascia: Diagnosis and Rehabilitative Therapeutic Intervention for Myofascial System Disorders. Bioengineering (Basel) 2023; 10:bioengineering10040474. [PMID: 37106661 PMCID: PMC10135675 DOI: 10.3390/bioengineering10040474] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Damage to the fascia can cause significant performance deficits in high-performance sports and recreational exercise and may contribute to the development of musculoskeletal disorders and persistent potential pain. The fascia is widely distributed from head to toe, encompassing muscles, bones, blood vessels, nerves, and internal organs and comprising various layers of different depths, indicating the complexity of its pathogenesis. It is a connective tissue composed of irregularly arranged collagen fibers, distinctly different from the regularly arranged collagen fibers found in tendons, ligaments, or periosteum, and mechanical changes in the fascia (stiffness or tension) can produce changes in its connective tissue that can cause pain. While these mechanical changes induce inflammation associated with mechanical loading, they are also affected by biochemical influences such as aging, sex hormones, and obesity. Therefore, this paper will review the current state of knowledge on the molecular level response to the mechanical properties of the fascia and its response to other physiological challenges, including mechanical changes, innervation, injury, and aging; imaging techniques available to study the fascial system; and therapeutic interventions targeting fascial tissue in sports medicine. This article aims to summarize contemporary views.
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Affiliation(s)
- Yuya Kodama
- Department of Orthopaedic Surgery, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Shin Masuda
- Department of Orthopaedic Surgery, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Toshinori Ohmori
- Department of Orthopaedic Surgery, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Akihiro Kanamaru
- Department of Orthopaedic Surgery, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Masato Tanaka
- Department of Orthopaedic Surgery, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Tomoyoshi Sakaguchi
- Department of Central Rehabilitation, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
| | - Masami Nakagawa
- Department of Central Rehabilitation, Okayama Rosai Hospital, 1-10-25 Midorimachi, Minamiku, Okayama 702-8055, Japan
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22
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Plaut S. “Long COVID-19” and viral “fibromyalgia-ness”: Suggesting a mechanistic role for fascial myofibroblasts (Nineveh, the shadow is in the fascia). Front Med (Lausanne) 2023; 10:952278. [PMID: 37089610 PMCID: PMC10117846 DOI: 10.3389/fmed.2023.952278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 02/27/2023] [Indexed: 04/08/2023] Open
Abstract
The coronavirus pandemic has led to a wave of chronic disease cases; “Long COVID-19” is recognized as a new medical entity and resembles “fibromyalgia” which, likewise, lacks a clear mechanism. Observational studies indicate that up to 30%–40% of convalescent COVID-19 patients develop chronic widespread pain and fatigue and fulfill the 2016 diagnostic criteria for “fibromyalgia.” A recent study suggested a theoretical neuro-biomechanical model (coined “Fascial Armoring”) to help explain the pathogenesis and cellular pathway of fibromyalgia, pointing toward mechanical abnormalities in connective tissue and fascia, driven by contractile myo/fibroblasts and altered extracellular matrix remodeling with downstream corresponding neurophysiological aberrations. This may help explain several of fibromyalgia’s manifestations such as pain, distribution of pain, trigger points/tender spots, hyperalgesia, chronic fatigue, cardiovascular abnormalities, metabolic abnormalities, autonomic abnormalities, small fiber neuropathy, various psychosomatic symptoms, lack of obvious inflammation, and silent imaging investigations. Pro-inflammatory and pro-fibrotic pathways provide input into this mechanism via stimulation of proto/myofibroblasts. In this hypothesis and theory paper the theoretical model of Fascial Armoring is presented to help explain the pathogenesis and manifestations of “long COVID-19” as a disease of immuno-rheumo-psycho-neurology. The model is also used to make testable experimental predictions on investigations and predict risk and relieving factors.
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23
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Benson LN, Guo Y, Deck K, Mora C, Liu Y, Mu S. The link between immunity and hypertension in the kidney and heart. Front Cardiovasc Med 2023; 10:1129384. [PMID: 36970367 PMCID: PMC10034415 DOI: 10.3389/fcvm.2023.1129384] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
Hypertension is the primary cause of cardiovascular disease, which is a leading killer worldwide. Despite the prevalence of this non-communicable disease, still between 90% and 95% of cases are of unknown or multivariate cause ("essential hypertension"). Current therapeutic options focus primarily on lowering blood pressure through decreasing peripheral resistance or reducing fluid volume, but fewer than half of hypertensive patients can reach blood pressure control. Hence, identifying unknown mechanisms causing essential hypertension and designing new treatment accordingly are critically needed for improving public health. In recent years, the immune system has been increasingly implicated in contributing to a plethora of cardiovascular diseases. Many studies have demonstrated the critical role of the immune system in the pathogenesis of hypertension, particularly through pro-inflammatory mechanisms within the kidney and heart, which, eventually, drive a myriad of renal and cardiovascular diseases. However, the precise mechanisms and potential therapeutic targets remain largely unknown. Therefore, identifying which immune players are contributing to local inflammation and characterizing pro-inflammatory molecules and mechanisms involved will provide promising new therapeutic targets that could lower blood pressure and prevent progression from hypertension into renal or cardiac dysfunction.
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Affiliation(s)
- Lance N. Benson
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, United States
| | | | | | | | | | - Shengyu Mu
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, United States
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24
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Dong XL, Yuan BH, Yu SZ, Liu H, Pan XH, Sun J, Pan LL. Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation. Acta Pharmacol Sin 2023; 44:573-583. [PMID: 36056082 PMCID: PMC9958096 DOI: 10.1038/s41401-022-00963-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 07/21/2022] [Indexed: 11/08/2022] Open
Abstract
Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-β1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-β1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.
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Affiliation(s)
- Xiao-Liang Dong
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Bao-Hui Yuan
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Sheng-Zhou Yu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - He Liu
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Xiao-Hua Pan
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Jia Sun
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China.
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122, China.
| | - Li-Long Pan
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
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25
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Concentration-Dependent Inhibition of Hypertrophic Scar Formation by Botulinum Toxin Type A in a Rabbit Ear Model. Aesthetic Plast Surg 2022; 46:3072-3079. [PMID: 35864206 DOI: 10.1007/s00266-022-03008-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/26/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hypertrophic scar (HS), as a disappointing result of wound healing, adversely affects the patient, both physically and psychologically. Botulinum toxin type A (BTXA) has been revealed to prevent and improve HS. We conducted this study to assess the effect of different BTXA concentrations on inhibiting HS in a rabbit ear model. METHODS Eight healthy New Zealand long-eared rabbits were included in the experiment for modeling. Four wounds of 1 cm in diameter were created on both ears, which separately received an injection of a given BTXA concentration immediately after surgery. On postoperative days 40, scar tissue was obtained and subjected to hematoxylin and eosin (HE) staining for the hypertrophic index (HI) and immunohistochemical staining for CD31, Ki67, and transforming growth factor-beta 1 (TGF-β1) expression. The HI was assessed for scar proliferation, and CD31 and Ki67 expression were used to assess the effect of BTXA on angiogenesis and fibroblast proliferation, respectively. RESULTS All rabbits healed well without infection or mortality. From the HE staining, the HI showed a significant decrease with increasing BTXA concentration (p < 0.05). BTXA also inhibited angiogenesis and TGF-β1 expression in a concentration-dependent manner, with significant differences between the groups (p < 0.05). BTXA inhibited fibroblast proliferation with increasing BTXA concentration. However, there was no significant difference between the 0.5 U/0.1 ml and 0 U/0.1 ml groups (p > 0.05). CONCLUSION Immediate postoperative BTXA injection inhibited angiogenesis, fibroblast proliferation, and TGF-β1 expression in a concentration-dependent manner, thus suppressing HS formation in rabbit ears. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/journal/00266 .
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26
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Raza GS, Sodum N, Kaya Y, Herzig KH. Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis. Int J Mol Sci 2022; 23:12954. [PMID: 36361737 PMCID: PMC9655416 DOI: 10.3390/ijms232112954] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 09/12/2023] Open
Abstract
Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.
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Affiliation(s)
- Ghulam Shere Raza
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Nalini Sodum
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Yagmur Kaya
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Marmara University, 34854 Istanbul, Turkey
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
- Oulu University Hospital, University of Oulu, 90220 Oulu, Finland
- Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, 60-572 Poznań, Poland
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Wang L, Feng J, Deng Y, Yang Q, Wei Q, Ye D, Rong X, Guo J. CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding. RESEARCH (WASHINGTON, D.C.) 2022; 2022:9891689. [PMID: 36299447 PMCID: PMC9575473 DOI: 10.34133/2022/9891689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/18/2022] [Indexed: 07/29/2023]
Abstract
CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.
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Affiliation(s)
- Lexun Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaojiao Feng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanyue Deng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qianqian Yang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Quxing Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dewei Ye
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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28
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Yue H, Liang W, Zhan Y, Zhang Z, Qin X, Bian L, He K, Wu Z. Colchicine: Emerging therapeutic effects on atrial fibrillation by alleviating myocardial fibrosis in a rat model. Biomed Pharmacother 2022; 154:113573. [PMID: 35987161 DOI: 10.1016/j.biopha.2022.113573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/07/2022] [Accepted: 08/15/2022] [Indexed: 11/19/2022] Open
Abstract
Although many research have found that colchicine has general therapeutic effect in cardiovascular disease, the therapeutic mechanism in atrial fibrillation has not been clearly studied. To explore whether colchicine plays a role in the treatment of AF by reducing myocardial fibrosis, we performed a series of studies. Rat models of AF were induced by Ach-CaCl2 to assess the therapeutic effect of colchicine at doses of 0.8 mg/kg on the duration of AF rhythm, degree of myocardial fibrosis, and secretion of inflammatory factors in the serum. RNA-Seq was also performed to elucidate the possible mechanisms by which colchicine might reduce the alleviation of myocardial fibrosis associated with AF. These studies showed that colchicine reduced the duration of AF and the degree of fibrosis in the left atrium and that it significantly reduced the secretion of TGFβ1, activin A, collagen I, and collagen III. These results suggest that colchicine may reduce myocardial fibrosis by (1) inhibiting the TGFβ1/ALK5 and activin A/ALK4 fibrosis pathways; (2) inhibiting the activation, phenotypic transformation, and apoptosis resistance of myocardial fibroblasts; and (3) reducing the synthesis of inflammatory factors and collagen.
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Affiliation(s)
- Honghua Yue
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Weitao Liang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Zhan
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zheng Zhang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Qin
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Longrong Bian
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Kang He
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhong Wu
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China.
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Wang H, Shi J, Shi S, Bo R, Zhang X, Hu Y. Bibliometric analysis on the progress of chronic heart failure. Curr Probl Cardiol 2022; 47:101213. [PMID: 35525461 DOI: 10.1016/j.cpcardiol.2022.101213] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/13/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic heart failure (CHF) is the terminal stage of a variety of heart diseases with higher morbidity and mortality. Although CHF has been studied for decades, the comprehensive analysis by bibliometrics has not been done. So, we analyzed the scientific outputs of global chronic heart failureresearches, explored the current research status and hotpots from 2009 to 2019. METHODS Web of Science Core Collection (WOSCC) was the data source, and the data was retrieved on June 25, 2020, according to the set search strategy. Bibliometrics tools- CiteSpace V (Drexel university, Chaomei Chen) and VOS viewer (Leiden University, van Eck NJ)-were used for analyzing published literature and exploring research hotspots and frontier directions. RESULTS A total of 21,484 articles were included, and the rate of published articles increased from 2009 to 2019 annually. United States of America (USA) was the leading country, Duke University was the leading institution, and Stefan D Anker was the most productive researcher in this field. The analysis of keywords showed that mortality, risk, outcomes, association, and dysfunction were the main hotpots and frontier directions of CHF. CONCLUSION Bibliometric analysis of the outputs on CHF shows an overall view about the current status of the research on CHF. Clinical treatment and the associations among organs in the patients with CHF are the major research frontiers. However, further research and collaboration are still required worldwide. Our findings can help researchers grasp the research status of CHF and determine new directions for future researches as soon as possible.
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Affiliation(s)
- Huan Wang
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingjing Shi
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shuqing Shi
- Graduate School, Beijing University of Chinese Medicine
| | - Rongqiang Bo
- Graduate School, Beijing University of Chinese Medicine
| | - Xuesong Zhang
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuanhui Hu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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LuQi Formula Ameliorates Myocardial Fibrosis by Suppressing TLR4/MyD88/NF- κB Pathway and NLRP3 Inflammasome Activation in Mice with Myocardial Infarction. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5867987. [PMID: 35310035 PMCID: PMC8933100 DOI: 10.1155/2022/5867987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 02/05/2022] [Accepted: 02/23/2022] [Indexed: 01/10/2023]
Abstract
Background Myocardial fibrosis caused by myocardial infarction (MI) is the key factor leading to cardiac remodeling; nod-like receptor family pyrin domain-containing 3 (NLRP3) plays an important role in regulation of myocardial injury; however, its relationship with TLR4/MyD88/NF-κB signaling pathway is largely unreported. In recent years, traditional Chinese medicine (TCM) prevention and treatment of cardiovascular diseases has shown its unique advantages and broad application prospects. LuQi Formula (LQF) has been used for more than 20 years in Shuguang Hospital (Shanghai, China), and it was confirmed that it can improve the clinical symptoms of patients after MI. Here, we investigated the mechanism of LQF by suppressing NLRP3 inflammasome activation and TLR4/MyD88/NF-κB pathway in mice with MI. Purpose The purpose of this study was to verify the positive effects of the LQF in ameliorating myocardial fibrosis and inflammasome infiltration in the MI mice in vivo. Methods Forty mice were randomized into four groups: the sham group, the MI group, the LQF group, and the perindopril group (n = 10 per group). Left anterior descending (LAD) coronary artery ligation was performed in all groups except the sham group. The mice were treated with LQF after MI. After 4 weeks, LDH, cTnI, IL-1β, and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA) kit, and cardiac function was evaluated by echocardiography. Hematoxylin and eosin (H&E) and Masson staining were used to evaluate the myocardial injury and fibrosis. Western blot was used to evaluate the expression of collagen I, α-SMA, NLRP3 inflammasome, and TLR4/MyD88/NF-κB signaling pathway. Immunohistochemical analysis was used to further detect the expression of Fibronectin, α-SMA, collagen I, collagen III, NLRP3, and NF-κB in myocardial tissue. Results Compared with the MI group, the ejection fraction (EF) and fractional shortening (FS) in the LQF group were significantly improved, while the left ventricular end diastolic diameter (LVEDd) and left ventricular internal dimension systole (LVIDs) were significantly decreased. The representative staining of H&E and Masson showed that treatment with LQF could effectively reduce myocardial injury and fibrosis. ELISA results showed that serum LDH, cTnI, TNF-α, IL-18, and IL-1β in LQF group were significantly lower than those in MI group. The western blot results showed that the expressions of collagen I and α-SMA were decreased significantly in the LQF group. Moreover, the expressions of NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling pathway were downregulated in the LQF treatment group. Conclusion Our results suggested that LQF could significantly improve cardiac function and ameliorate myocardial fibrosis. In addition, we found that LQF could downregulate the TLR4/MyD88/NF-κB signaling pathway and then inhibit the activation of NLRP3 inflammasome, suggesting that LQF alleviated cardiac fibrosis by decreasing the TLR4/MyD88/NF-κB signaling pathway and then inhibited NLRP3 inflammasome activation in MI mice, which indicates potential therapeutic effect of LQF on patients with MI.
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Sulaiman A, Chambers J, Chilumula SC, Vinod V, Kandunuri R, McGarry S, Kim S. At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy. Cancers (Basel) 2022; 14:1577. [PMID: 35326728 PMCID: PMC8946238 DOI: 10.3390/cancers14061577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/13/2022] [Accepted: 03/17/2022] [Indexed: 02/01/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.
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Affiliation(s)
- Andrew Sulaiman
- Department of Basic Science, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106, USA; (S.C.C.); (V.V.); (R.K.); (S.K.)
| | - Jason Chambers
- Schulich School of Medicine, Western University, London, ON N6A5C1, Canada;
| | - Sai Charan Chilumula
- Department of Basic Science, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106, USA; (S.C.C.); (V.V.); (R.K.); (S.K.)
| | - Vishak Vinod
- Department of Basic Science, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106, USA; (S.C.C.); (V.V.); (R.K.); (S.K.)
| | - Rohith Kandunuri
- Department of Basic Science, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106, USA; (S.C.C.); (V.V.); (R.K.); (S.K.)
| | - Sarah McGarry
- Children’s Mercy Hospital Kansas City, 2401 Gillham Rd, Kansas City, MO 64108, USA;
| | - Sung Kim
- Department of Basic Science, Kansas City University, 1750 Independence Ave, Kansas City, MO 64106, USA; (S.C.C.); (V.V.); (R.K.); (S.K.)
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Duong TE, Wu Y, Sos BC, Dong W, Limaye S, Rivier LH, Myers G, Hagood JS, Zhang K. A single-cell regulatory map of postnatal lung alveologenesis in humans and mice. CELL GENOMICS 2022; 2:100108. [PMID: 35434692 PMCID: PMC9012447 DOI: 10.1016/j.xgen.2022.100108] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 05/05/2021] [Accepted: 02/02/2022] [Indexed: 04/14/2023]
Abstract
Ex-utero regulation of the lungs' responses to breathing air and continued alveolar development shape adult respiratory health. Applying single-cell transposome hypersensitive site sequencing (scTHS-seq) to over 80,000 cells, we assembled the first regulatory atlas of postnatal human and mouse lung alveolar development. We defined regulatory modules and elucidated new mechanistic insights directing alveolar septation, including alveolar type 1 and myofibroblast cell signaling and differentiation, and a unique human matrix fibroblast population. Incorporating GWAS, we mapped lung function causal variants to myofibroblasts and identified a pathogenic regulatory unit linked to lineage marker FGF18, demonstrating the utility of chromatin accessibility data to uncover disease mechanism targets. Our regulatory map and analysis model provide valuable new resources to investigate age-dependent and species-specific control of critical developmental processes. Furthermore, these resources complement existing atlas efforts to advance our understanding of lung health and disease across the human lifespan.
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Affiliation(s)
- Thu Elizabeth Duong
- Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Yan Wu
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Brandon Chin Sos
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Weixiu Dong
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Siddharth Limaye
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Lauraine H. Rivier
- Department of Pediatrics, Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Greg Myers
- Department of Pediatrics, Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - James S. Hagood
- Department of Pediatrics, Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Kun Zhang
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
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Bugg D, Bailey LRJ, Bretherton RC, Beach KE, Reichardt IM, Robeson KZ, Reese AC, Gunaje J, Flint G, DeForest CA, Stempien-Otero A, Davis J. MBNL1 drives dynamic transitions between fibroblasts and myofibroblasts in cardiac wound healing. Cell Stem Cell 2022; 29:419-433.e10. [PMID: 35176223 PMCID: PMC8929295 DOI: 10.1016/j.stem.2022.01.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 11/30/2021] [Accepted: 01/24/2022] [Indexed: 12/18/2022]
Abstract
Dynamic fibroblast to myofibroblast state transitions underlie the heart's fibrotic response. Because transcriptome maturation by muscleblind-like 1 (MBNL1) promotes differentiated cell states, this study investigated whether tactical control of MBNL1 activity could alter myofibroblast activity and fibrotic outcomes. In healthy mice, cardiac fibroblast-specific overexpression of MBNL1 transitioned the fibroblast transcriptome to that of a myofibroblast and after injury promoted myocyte remodeling and scar maturation. Both fibroblast- and myofibroblast-specific loss of MBNL1 limited scar production and stabilization, which was ascribed to negligible myofibroblast activity. The combination of MBNL1 deletion and injury caused quiescent fibroblasts to expand and adopt features of cardiac mesenchymal stem cells, whereas transgenic MBNL1 expression blocked fibroblast proliferation and drove the population into a mature myofibroblast state. These data suggest MBNL1 is a post-transcriptional switch, controlling fibroblast state plasticity during cardiac wound healing.
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Affiliation(s)
- Darrian Bugg
- Department of Lab Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
| | - Logan R J Bailey
- Molecular & Cellular Biology, University of Washington, Seattle, WA 98195, USA
| | - Ross C Bretherton
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - Kylie E Beach
- Department of Lab Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
| | | | - Kalen Z Robeson
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - Anna C Reese
- Department of Lab Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
| | - Jagadambika Gunaje
- Department of Lab Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
| | - Galina Flint
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - Cole A DeForest
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA; Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA
| | | | - Jennifer Davis
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA; Department of Lab Medicine & Pathology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
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Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells 2022; 14:200-213. [PMID: 35432731 PMCID: PMC8963379 DOI: 10.4252/wjsc.v14.i2.200] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sustained injury, through radiotherapy, burns or surgical trauma, can result in fibrosis, displaying an excessive deposition of extracellular matrix (ECM), persisting inflammatory reaction, and reduced vascularization. The increasing recognition of fibrosis as a cause for disease and mortality, and increasing use of radiotherapy causing fibrosis, stresses the importance of a decent anti-fibrotic treatment.
AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of adipose-derived stomal cells (ADSCs) in realizing their anti-fibrotic effect.
METHODS A systematic review of the literature using PubMed, Embase and Web of Science was performed by two independent reviewers.
RESULTS The injection of fat grafts into fibrotic tissue, releases ADSC into the environment. ADSCs’ capacity to directly differentiate into key cell types (e.g., ECs, fibroblasts), as well as to secrete multiple paracrine factors (e.g., hepatocyte growth factor, basis fibroblast growth factor, IL-10), allows them to alter different mechanisms underlying fibrosis in a combined approach. ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation, favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases, positively influencing collagen organization, and inhibiting the pro-fibrotic effects of transforming growth factor-β1. Furthermore, they impact elements of both the innate and adaptive immune response system, and stimulate angiogenesis on the site of injury (through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).
CONCLUSION This review shows that understanding the complex interactions of ECM accumulation, immune response and vascularization, is vital to fibrosis treatments’ effectiveness like fat grafting. It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction, without falling into extreme dilation or stimulation of a single aspect. Detailing this combined approach, has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.
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Affiliation(s)
| | - Jan Jeroen Vranckx
- Department of Plastic, Reconstructive Surgery, KU-Leuven University Hospitals, Leuven 3000, Belgium
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Plaut S. Scoping review and interpretation of myofascial pain/fibromyalgia syndrome: An attempt to assemble a medical puzzle. PLoS One 2022; 17:e0263087. [PMID: 35171940 PMCID: PMC8849503 DOI: 10.1371/journal.pone.0263087] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 01/11/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Myofascial Pain Syndrome (MPS) is a common, overlooked, and underdiagnosed condition and has significant burden. MPS is often dismissed by clinicians while patients remain in pain for years. MPS can evolve into fibromyalgia, however, effective treatments for both are lacking due to absence of a clear mechanism. Many studies focus on central sensitization. Therefore, the purpose of this scoping review is to systematically search cross-disciplinary empirical studies of MPS, focusing on mechanical aspects, and suggest an organic mechanism explaining how it might evolve into fibromyalgia. Hopefully, it will advance our understanding of this disease. METHODS Systematically searched multiple phrases in MEDLINE, EMBASE, COCHRANE, PEDro, and medRxiv, majority with no time limit. Inclusion/exclusion based on title and abstract, then full text inspection. Additional literature added on relevant side topics. Review follows PRISMA-ScR guidelines. PROSPERO yet to adapt registration for scoping reviews. FINDINGS 799 records included. Fascia can adapt to various states by reversibly changing biomechanical and physical properties. Trigger points, tension, and pain are a hallmark of MPS. Myofibroblasts play a role in sustained myofascial tension. Tension can propagate in fascia, possibly supporting a tensegrity framework. Movement and mechanical interventions treat and prevent MPS, while living sedentarily predisposes to MPS and recurrence. CONCLUSIONS MPS can be seen as a pathological state of imbalance in a natural process; manifesting from the inherent properties of the fascia, triggered by a disrupted biomechanical interplay. MPS might evolve into fibromyalgia through deranged myofibroblasts in connective tissue ("fascial armoring"). Movement is an underemployed requisite in modern lifestyle. Lifestyle is linked to pain and suffering. The mechanism of needling is suggested to be more mechanical than currently thought. A "global percutaneous needle fasciotomy" that respects tensegrity principles may treat MPS/fibromyalgia more effectively. "Functional-somatic syndromes" can be seen as one entity (myofibroblast-generated-tensegrity-tension), sharing a common rheuma-psycho-neurological mechanism.
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Affiliation(s)
- Shiloh Plaut
- School of Medicine, St. George’s University of London, London, United Kingdom
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Aguado BA, Walker CJ, Grim JC, Schroeder ME, Batan D, Vogt BJ, Rodriguez AG, Schwisow JA, Moulton KS, Weiss RM, Heistad DD, Leinwand LA, Anseth KS. Genes That Escape X Chromosome Inactivation Modulate Sex Differences in Valve Myofibroblasts. Circulation 2022; 145:513-530. [PMID: 35000411 PMCID: PMC8844107 DOI: 10.1161/circulationaha.121.054108] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Aortic valve stenosis is a sexually dimorphic disease, with women often presenting with sustained fibrosis and men with more extensive calcification. However, the intracellular molecular mechanisms that drive these clinically important sex differences remain underexplored. METHODS Hydrogel biomaterials were designed to recapitulate key aspects of the valve tissue microenvironment and to serve as a culture platform for sex-specific valvular interstitial cells (VICs; precursors to profibrotic myofibroblasts). The hydrogel culture system was used to interrogate intracellular pathways involved in sex-dependent VIC-to-myofibroblast activation and deactivation. RNA sequencing was used to define pathways involved in driving sex-dependent activation. Interventions with small molecule inhibitors and siRNA transfections were performed to provide mechanistic insight into sex-specific cellular responses to microenvironmental cues, including matrix stiffness and exogenously delivered biochemical factors. RESULTS In both healthy porcine and human aortic valves, female leaflets had higher baseline activation of the myofibroblast marker α-smooth muscle actin compared with male leaflets. When isolated and cultured, female porcine and human VICs had higher levels of basal α-smooth muscle actin stress fibers that further increased in response to the hydrogel matrix stiffness, both of which were higher than in male VICs. A transcriptomic analysis of male and female porcine VICs revealed Rho-associated protein kinase signaling as a potential driver of this sex-dependent myofibroblast activation. Furthermore, we found that genes that escape X-chromosome inactivation such as BMX and STS (encoding for Bmx nonreceptor tyrosine kinase and steroid sulfatase, respectively) partially regulate the elevated female myofibroblast activation through Rho-associated protein kinase signaling. This finding was confirmed by treating male and female VICs with endothelin-1 and plasminogen activator inhibitor-1, factors that are secreted by endothelial cells and known to drive myofibroblast activation through Rho-associated protein kinase signaling. CONCLUSIONS Together, in vivo and in vitro results confirm sex dependencies in myofibroblast activation pathways and implicate genes that escape X-chromosome inactivation in regulating sex differences in myofibroblast activation and subsequent aortic valve stenosis progression. Our results underscore the importance of considering sex as a biological variable to understand the molecular mechanisms of aortic valve stenosis and to help guide sex-based precision therapies.
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Affiliation(s)
- Brian A. Aguado
- Department of Chemical and Biological Engineering, University of Colorado Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Cierra J. Walker
- Materials Science and Engineering Program, University of Colorado Boulder, CO 80309, USA
- Department of Biochemistry, University of Colorado Boulder, CO 80303, USA
| | - Joseph C. Grim
- Department of Chemical and Biological Engineering, University of Colorado Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
| | - Megan E. Schroeder
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
- Materials Science and Engineering Program, University of Colorado Boulder, CO 80309, USA
| | - Dilara Batan
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
- Department of Biochemistry, University of Colorado Boulder, CO 80303, USA
| | - Brandon J. Vogt
- Department of Chemical and Biological Engineering, University of Colorado Boulder, CO 80303, USA
- Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
| | - Andrea Gonzalez Rodriguez
- Department of Chemical and Biological Engineering, University of Colorado Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
| | - Jessica A. Schwisow
- Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Karen S. Moulton
- Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Robert M. Weiss
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
| | - Donald D. Heistad
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242
| | - Leslie A. Leinwand
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, CO 80309, USA
| | - Kristi S. Anseth
- Department of Chemical and Biological Engineering, University of Colorado Boulder, CO 80303, USA
- BioFrontiers Institute, University of Colorado Boulder, CO 80309, USA
- Materials Science and Engineering Program, University of Colorado Boulder, CO 80309, USA
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Qin YY, Huang XR, Zhang J, Wu W, Chen J, Wan S, Yu XY, Lan HY. Neuropeptide Y attenuates cardiac remodeling and deterioration of function following myocardial infarction. Mol Ther 2022; 30:881-897. [PMID: 34628054 PMCID: PMC8821956 DOI: 10.1016/j.ymthe.2021.10.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/29/2021] [Accepted: 09/30/2021] [Indexed: 02/04/2023] Open
Abstract
Plasma levels of neuropeptide Y (NPY) are elevated in patients with acute myocardial infarction (AMI), but its role in AMI remains unclear, which was examined here in NPY wild-type/knockout (WT/KO) mice treated with/without exogenous NPY and its Y1 receptor antagonist (Y1Ra) BIBP 3226. We found that AMI mice lacking NPY developed more severe AMI than WT mice with worse cardiac dysfunction, progressive cardiac inflammation and fibrosis, and excessive apoptosis but impairing angiogenesis. All of these changes were reversed when the NPY KO mice were treated with exogenous NPY in a dose-dependent manner. Interestingly, treatment with NPY also dose dependently attenuated AMI in WT mice, which was blocked by BIBP 3226. Phenotypically, cardiac NPY was de novo expressed by infiltrating macrophages during the repairing or fibrosing process in heart-failure patients and AMI mice. Mechanistically, NPY was induced by transforming growth factor (TGF)-β1 in bone marrow-derived macrophages and signaled through its Y1R to exert its pathophysiological activities by inhibiting p38/nuclear factor κB (NF-κB)-mediated M1 macrophage activation while promoting the reparative M2 phenotype in vivo and in vitro. In conclusion, NPY can attenuate AMI in mice. Inhibition of cardiac inflammation and fibrosis while enhancing angiogenesis but reducing apoptosis may be the underlying mechanisms through which NPY attenuates cardiac remodeling and deterioration of function following AMI.
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Affiliation(s)
- Yu-Yan Qin
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China; Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China; Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Jian Zhang
- Department of Cardiovascular Surgery, Shenyang Northern Hospital, No. 83, Wenhua Road, Shenhe District, Shenyang, Liaoning, China
| | - Wenjing Wu
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
| | - Junzhe Chen
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China
| | - Song Wan
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Xi-Yong Yu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China; The Chinese University of Hong Kong (CUHK)-Guangdong Provincial People's Hospital Joint Research Laboratory on Immunological and Genetic Kidney Diseases, CUHK, Hong Kong, China.
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Rubiś P, Totoń-Żurańska J, Kołton-Wróż M, Wołkow P, Pitera E, Wiśniowska-Śmiałek S, Dziewięcka E, Garlitski A, Podolec P. Twelve-month kinetics of circulating fibrosis-linked microRNAs (miR-21, miR-29, miR-30, and miR-133a) and the relationship with extracellular matrix fibrosis in dilated cardiomyopathy. Arch Med Sci 2022; 18:480-488. [PMID: 35316894 PMCID: PMC8924829 DOI: 10.5114/aoms.2019.89777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/07/2019] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION A single measurement of any biomarker may not reflect its full biological meaning. The kinetics of fibrosis-linked microRNAs and their relationship with extracellular matrix (ECM) fibrosis in dilated cardiomyopathy (DCM) have not been explored. MATERIAL AND METHODS We evaluated 70 consecutive DCM patients (48 ±12.1 years, left ventricular ejection fraction 24.4 ±7.4%). All patients underwent right ventricular endomyocardial biopsy in order to quantify ECM fibrosis and measure collagen volume fraction (CVF). Circulating microRNAs (miR-21-5p, miR-29b, miR-30c-5p, and miR-133a-3p) were measured with quantitative polymerase chain reaction (PCR) at baseline and at 3 and 12 months. RESULTS Based on the biopsy results, two groups of patients were identified: with (n = 24, 34.3%) and without (n = 46, 65.7%) ECM fibrosis. Except for a single measurement of miR-29b at 3 months (DCM with fibrosis: 6.03 ±0.72 vs. DCM without fibrosis: 6.4 ±0.75 ΔCq; p < 0.05), baseline, 3- and 12-month kinetics of microRNAs did not differ between the two groups. Moreover, 12-month microRNA kinetics did not differ in patients with new-onset DCM (duration < 6 months; n = 35) and chronic DCM (> 6 months; n = 35). Only miR-29 at 3 months correlated with CVF (r = -0.31; p < 0.05), whereas other microRNAs did not correlate with CVF either at 3 or at 12 months. CONCLUSIONS Regardless of ECM fibrosis status or duration of the disease, 12-month patterns of circulating microRNAs are similar in DCM. Correlations between microRNAs, measured at 3 and 12 months, are lower than expected. In this study, regardless of the time point, circulating microRNAs were not able to differentiate between DCM patients with versus without fibrosis.
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Affiliation(s)
- Paweł Rubiś
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Justyna Totoń-Żurańska
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Maria Kołton-Wróż
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Paweł Wołkow
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Ewelina Pitera
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Sylwia Wiśniowska-Śmiałek
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Ewa Dziewięcka
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
| | | | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
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Shao T, Xue Y, Fang M. Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis. Front Cell Dev Biol 2021; 9:771466. [PMID: 34869368 PMCID: PMC8633401 DOI: 10.3389/fcell.2021.771466] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between -516 and -224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.
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Affiliation(s)
- Tinghui Shao
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yujia Xue
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Mingming Fang
- Center for Experimental Medicine, Jiangsu Health Vocational College, Nanjing, China.,Institute of Biomedical Research, Liaocheng University, Liaocheng, China
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Wang F, Hu R, Zhang J, Pei T, He Z, Ju L, Han Z, Wang M, Xiao W. High-dose vitamin D3 supplementation ameliorates renal fibrosis by vitamin D receptor activation and inhibiting TGF-β1/Smad3 signaling pathway in 5/6 nephrectomized rats. Eur J Pharmacol 2021; 907:174271. [PMID: 34147475 DOI: 10.1016/j.ejphar.2021.174271] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/09/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022]
Abstract
Renal fibrosis is the pathological consequence of progressive chronic kidney disease. Although it has been reported that vitamin D3 exerts antifibrotic effects, the underlying mechanisms remain unclear. This study is aimed at investigating the effects and molecular mechanisms in high-dose vitamin D3 treatment on renal fibrosis. A model of chronic kidney disease was established by 5/6 nephrectomy in rats characterised by high levels of serum creatine, urea nitrogen, and urinary protein. Serum 25-dihydroxyvitamin D3, calcium and parathormone levels were measured to evaluate vitamin D levels. Hematoxylin and eosin, periodic acid Schiff and Mallory's Trichrome staining were used to evaluate histopathological changes in rats. Moreover, the expression of vimentin, collagen I, α-smooth muscle actin and E-cadherin were analyzed at molecular and histopathological levels. Our results showed that exposure to vitamin D3 decreased the levels of serum creatine, urea nitrogen and urine protein and restored the homeostasis of calcium and parathormone. Vitamin D3 also downregulated the expression of vimentin, collagen I and α-smooth muscle actin and attenuated renal fibrosis and epithelial to mesenchymal transition in the kidney. Importantly, vitamin D3 treatment increased the expression of the vitamin D receptor and inhibited Transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway in rats kidneys with chronic kidney disease. Mechanistically, the upregulation of TGF-β1 and phosphorylation of Smad3 induced by vitamin D3 was reversed by activation of the vitamin D receptor. Our findings indicated that vitamin D3 is a potential antifibrotic drug in chronic kidney disease via the vitmin D receptor and inhibiting TGF-β1/Smad3 signaling pathway.
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Affiliation(s)
- Fujing Wang
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Rong Hu
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaxing Zhang
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Tingting Pei
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhuo'en He
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Liliang Ju
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongxiao Han
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Mingqing Wang
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
| | - Wei Xiao
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
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41
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Zhang Y, Lin X, Chu Y, Chen X, Du H, Zhang H, Xu C, Xie H, Ruan Q, Lin J, Liu J, Zeng J, Ma K, Chai D. Dapagliflozin: a sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFβ1/Smad signaling. Cardiovasc Diabetol 2021; 20:121. [PMID: 34116674 PMCID: PMC8196449 DOI: 10.1186/s12933-021-01312-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/03/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. METHODS Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 μM) with or without the indicated concentration (0.5, 1, 10 μM) of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes. RESULTS DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling. CONCLUSION DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a non-glucose-lowering dependent manner.
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MESH Headings
- Angiotensin II
- Animals
- Antifibrotic Agents/pharmacology
- Benzhydryl Compounds/pharmacology
- Cells, Cultured
- Disease Models, Animal
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Fibrosis
- Glucosides/pharmacology
- Hypertrophy, Left Ventricular/chemically induced
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Hypertrophy, Left Ventricular/prevention & control
- Male
- Myocardium/metabolism
- Myocardium/pathology
- Rats, Sprague-Dawley
- Signal Transduction
- Smad Proteins/metabolism
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Transforming Growth Factor beta1/metabolism
- Ventricular Dysfunction, Left/chemically induced
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/pathology
- Ventricular Dysfunction, Left/prevention & control
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
- Rats
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Affiliation(s)
- Yuze Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Xiaoyan Lin
- Echocardiological Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Yong Chu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Xiaoming Chen
- Editorial Department of Chinese Journal of Hypertension, Fuzhou, 350005, China
| | - Heng Du
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Hailin Zhang
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Changsheng Xu
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Hong Xie
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Qinyun Ruan
- Echocardiological Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Jinxiu Lin
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China
| | - Jie Liu
- School of Pharmacy College, Xiamen University, Xiamen, 361102, China
| | - Jinzhang Zeng
- School of Pharmacy College, Xiamen University, Xiamen, 361102, China
| | - Ke Ma
- Clinical Research Center, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
| | - Dajun Chai
- Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fujian Institute of Hypertension, 20 Chazhong Road, Fuzhou, 350005, China.
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Proteome Characterization of BALF Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Unveiling Undercover Molecular Pathways. Int J Mol Sci 2021; 22:ijms22115696. [PMID: 34071777 PMCID: PMC8199247 DOI: 10.3390/ijms22115696] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/24/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
In the longtime challenge of identifying specific, easily detectable and reliable biomarkers of IPF, BALF proteomics is providing interesting new insights into its pathogenesis. To the best of our knowledge, the present study is the first shotgun proteomic investigation of EVs isolated from BALF of IPF patients. Our main aim was to characterize the proteome of the vesicular component of BALF and to explore its individual impact on the pathogenesis of IPF. To this purpose, ultracentrifugation was chosen as the EVs isolation technique, and their purification was assessed by TEM, 2DE and LC-MS/MS. Our 2DE data and scatter plots showed considerable differences between the proteome of EVs and that of whole BALF and of its fluid component. Analysis of protein content and protein functions evidenced that EV proteins are predominantly involved in cytoskeleton remodeling, adenosine signaling, adrenergic signaling, C-peptide signaling and lipid metabolism. Our findings may suggest a wider system involvement in the disease pathogenesis and support the importance of pre-fractioning of complex samples, such as BALF, in order to let low-abundant proteins-mediated pathways emerge.
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43
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Collagen denaturation in the infarcted myocardium involves temporally distinct effects of MT1-MMP-dependent proteolysis and mechanical tension. Matrix Biol 2021; 99:18-42. [PMID: 34048934 DOI: 10.1016/j.matbio.2021.05.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022]
Abstract
Tissue injury results in profound alterations in the collagen network, associated with unfolding of the collagen triple helix, proteolytic degradation and generation of fragments. In the infarcted myocardium, changes in the collagen network are critically involved in the pathogenesis of left ventricular rupture, adverse remodeling and chronic dysfunction. We hypothesized that myocardial infarction is associated with temporally and spatially restricted patterns of collagen denaturation that may reflect distinct molecular mechanisms of collagen unfolding. We used a mouse model of non-reperfused myocardial infarction, and in vitro assays in fibroblast-populated collagen lattices. In healing infarcts, labeling with collagen hybridizing peptide (CHP) revealed two distinct patterns of collagen denaturation. During the inflammatory and proliferative phases of infarct healing, collagen denaturation was pericellular, localized in close proximity to macrophages and myofibroblasts. qPCR array analysis of genes associated with matrix remodeling showed that Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) is markedly upregulated in infarct macrophages and fibroblasts, suggesting its involvement in pericellular collagen denaturation. In vitro, MT1-MMP-mediated pericellular collagen denaturation is involved in cardiac fibroblast migration. The effects of MT1-MMP on collagen denaturation and fibroblast migration involve the catalytic site, and require hemopexin domain-mediated actions. In contrast, during the maturation phase of infarct healing, extensive collagen denaturation was noted in the hypocellular infarct, in the infarct border zone and in the mitral valve annulus, in the absence of MT1-MMP. In vitro, mechanical tension in attached collagen lattices was sufficient to induce peripheral collagen denaturation. Our study suggests that in healing infarcts, early pericellular collagen denaturation may be important for migration of macrophages and reparative myofibroblasts in the infarct. Extensive denaturation of collagen fibers is noted in mature scars, likely reflecting mechanical tension. Chronic collagen denaturation may increase susceptibility of the matrix to proteolysis, thus contributing to progressive cardiac dilation and post-infarction heart failure.
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Romano E, Rosa I, Fioretto BS, Cerinic MM, Manetti M. The Role of Pro-fibrotic Myofibroblasts in Systemic Sclerosis: from Origin to Therapeutic Targeting. Curr Mol Med 2021; 22:209-239. [PMID: 33823766 DOI: 10.2174/0929867328666210325102749] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 03/02/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022]
Abstract
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disorder characterized by multisystem clinical manifestations resulting from immune dysregulation/autoimmunity, vasculopathy and, most notably, progressive fibrosis of the skin and internal organs. In recent years, it has emerged that the main drivers of SSc-related tissue fibrosis are myofibroblasts, a type of mesenchymal cells with both the extracellular matrix-synthesizing features of fibroblasts and the cytoskeletal characteristics of contractile smooth muscle cells. The accumulation and persistent activation of pro-fibrotic myofibroblasts during SSc development and progression result into elevated mechanical stress and reduced matrix plasticity within the affected tissues and may be ascribed to a reduced susceptibility of these cells to pro-apoptotic stimuli, as well as their increased formation from tissue-resident fibroblasts or transition from different cell types. Given the crucial role of myofibroblasts in SSc pathogenesis, finding the way to inhibit myofibroblast differentiation and accumulation by targeting their formation, function and survival may represent an effective approach to hamper the fibrotic process or even halt or reverse established fibrosis. In this review, we discuss the role of myofibroblasts in SSc-related fibrosis, with a special focus on their cellular origin and the signaling pathways implicated in their formation and persistent activation. Furthermore, we provide an overview of potential therapeutic strategies targeting myofibroblasts that may be able to counteract fibrosis in this pathological condition.
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Affiliation(s)
- Eloisa Romano
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Irene Rosa
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Bianca Saveria Fioretto
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Marco Matucci Cerinic
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Mirko Manetti
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence. Italy
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Yang J, Zhang Y, Qin M, Cheng W, Wang W, Cao Y. Understanding and Regulating Cell-Matrix Interactions Using Hydrogels of Designable Mechanical Properties. J Biomed Nanotechnol 2021; 17:149-168. [PMID: 33785089 DOI: 10.1166/jbn.2021.3026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Similar to natural tissues, hydrogels contain abundant water, so they are considered as promising biomaterials for studying the influence of the mechanical properties of extracellular matrices (ECM) on various cell functions. In recent years, the growing research on cellular mechanical response has revealed that many cell functions, including cell spreading, migration, tumorigenesis and differentiation, are related to the mechanical properties of ECM. Therefore, how cells sense and respond to the extracellular mechanical environment has gained considerable attention. In these studies, hydrogels are widely used as the in vitro model system. Hydrogels of tunable stiffness, viscoelasticity, degradability, plasticity, and dynamical properties have been engineered to reveal how cells respond to specific mechanical features. In this review, we summarize recent process in this research direction and specifically focus on the influence of the mechanical properties of the ECM on cell functions, how cells sense and respond to the extracellular mechanical environment, and approaches to adjusting the stiffness of hydrogels.
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Affiliation(s)
- Jiapeng Yang
- Key Laboratory of Intelligent Optical Sensing and Integration, National Laboratory of Solid State Microstructure, and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Yu Zhang
- Key Laboratory of Intelligent Optical Sensing and Integration, National Laboratory of Solid State Microstructure, and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Meng Qin
- Key Laboratory of Intelligent Optical Sensing and Integration, National Laboratory of Solid State Microstructure, and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Wei Cheng
- Department of Oral Implantology Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Wei Wang
- Key Laboratory of Intelligent Optical Sensing and Integration, National Laboratory of Solid State Microstructure, and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
| | - Yi Cao
- Key Laboratory of Intelligent Optical Sensing and Integration, National Laboratory of Solid State Microstructure, and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093, China
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Kostecki GM, Shi Y, Chen CS, Reich DH, Entcheva E, Tung L. Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes. Sci Rep 2021; 11:4430. [PMID: 33627695 PMCID: PMC7904933 DOI: 10.1038/s41598-021-83398-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 01/27/2021] [Indexed: 01/31/2023] Open
Abstract
Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the extent of myofibroblast-myocyte electrical conductance in a syncytium is unknown. In this neonatal rat study, cardiac myofibroblasts were transduced with Channelrhodopsin-2, which allowed acute and selective increase of myofibroblast current, and plated on top of cardiomyocytes. Optical mapping revealed significantly decreased conduction velocity (- 27 ± 6%, p < 10-3), upstroke rate (- 13 ± 4%, p = 0.002), and action potential duration (- 14 ± 7%, p = 0.004) in co-cultures when 0.017 mW/mm2 light was applied, as well as focal spontaneous beating in 6/7 samples and a decreased cycle length (- 36 ± 18%, p = 0.002) at 0.057 mW/mm2 light. In silico modeling of the experiments reproduced the experimental findings and suggested the light levels used in experiments produced excess current similar in magnitude to endogenous myofibroblast current. Fitting the model to experimental data predicted a tissue-level electrical conductance across the 3-D interface between myofibroblasts and cardiomyocytes of ~ 5 nS/cardiomyocyte, and showed how increased myofibroblast-myocyte conductance, increased myofibroblast/myocyte capacitance ratio, and increased myofibroblast current, which occur in fibrosis, can work in tandem to produce pro-arrhythmic increases in conduction and spontaneous beating.
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Affiliation(s)
- Geran M Kostecki
- Department of Biomedical Engineering, Johns Hopkins University, 720 Rutland Ave., Baltimore, MD, 21205, USA
| | - Yu Shi
- Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Christopher S Chen
- Biological Design Center, Department of Biomedical Engineering, Boston University, Boston, MA, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Daniel H Reich
- Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Emilia Entcheva
- Department of Biomedical Engineering, George Washington University, Washington, DC, USA
| | - Leslie Tung
- Department of Biomedical Engineering, Johns Hopkins University, 720 Rutland Ave., Baltimore, MD, 21205, USA.
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Zivarpour P, Reiner Ž, Hallajzadeh J, Mirsafaei L. Resveratrol and cardiac fibrosis prevention and treatment. Curr Pharm Biotechnol 2021; 23:190-200. [PMID: 33583368 DOI: 10.2174/1389201022666210212125003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/17/2020] [Accepted: 12/23/2020] [Indexed: 11/22/2022]
Abstract
Cardiovascular diseases are some of the major causes of morbidity and mortality in developed or developing countries but in developed countries as well. Cardiac fibrosis is one of the most often pathological changes of heart tissues. It occurs as a result of extracellular matrix proteins accumulation at myocardia. Cardiac fibrosis results in impaired cardiac systolic and diastolic functions and is associated with other effects. Therapies with medicines have not been sufficiently successful in treating chronic diseases such as CVD. Therefore, the interest for therapeutic potential of natural compounds and medicinal plants has increased. Plants such as grapes, berries and peanuts contain a polyphenolic compound called "resveratrol" which has been reported to have various therapeutic properties for a variety of diseases. Studies on laboratory models that show that resveratrol has beneficial effects on cardiovascular diseases including myocardial infarction, high blood pressure cardiomyopathy, thrombosis, cardiac fibrosis, and atherosclerosis. In vitro animal models using resveratrol indicated protective effects on the heart by neutralizing reactive oxygen species, preventing inflammation, increasing neoangiogenesis, dilating blood vessels, suppressing apoptosis and delaying atherosclerosis. In this review, we are presenting experimental and clinical results of studies concerning resveratrol effects on cardiac fibrosis as a CVD outcome in humans.
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Affiliation(s)
- Parinaz Zivarpour
- Department of Biological sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz. Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb. Croatia
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Science, Maragheh. Iran
| | - Liaosadat Mirsafaei
- Department of Cardiology, Ramsar Campus, Mazandaran University of Medical Sciences, Sari. Iran
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Cardiac cell type-specific responses to injury and contributions to heart regeneration. CELL REGENERATION 2021; 10:4. [PMID: 33527149 PMCID: PMC7851195 DOI: 10.1186/s13619-020-00065-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/13/2020] [Indexed: 12/13/2022]
Abstract
Heart disease is the leading cause of mortality worldwide. Due to the limited proliferation rate of mature cardiomyocytes, adult mammalian hearts are unable to regenerate damaged cardiac muscle following injury. Instead, injured area is replaced by fibrotic scar tissue, which may lead to irreversible cardiac remodeling and organ failure. In contrast, adult zebrafish and neonatal mammalian possess the capacity for heart regeneration and have been widely used as experimental models. Recent studies have shown that multiple types of cells within the heart can respond to injury with the activation of distinct signaling pathways. Determining the specific contributions of each cell type is essential for our understanding of the regeneration network organization throughout the heart. In this review, we provide an overview of the distinct functions and coordinated cell behaviors of several major cell types including cardiomyocytes, endocardial cells, epicardial cells, fibroblasts, and immune cells. The topic focuses on their specific responses and cellular plasticity after injury, and potential therapeutic applications.
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Eguchi A, Coleman R, Gresham K, Gao E, Ibetti J, Chuprun JK, Koch WJ. GRK5 is a regulator of fibroblast activation and cardiac fibrosis. Proc Natl Acad Sci U S A 2021; 118:e2012854118. [PMID: 33500351 PMCID: PMC7865138 DOI: 10.1073/pnas.2012854118] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pathological remodeling of the heart is a hallmark of chronic heart failure (HF) and these structural changes further perpetuate the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the heart. Stress conditions, such as a myocardial infarction (MI), can activate quiescent fibroblasts into synthetic and contractile myofibroblasts. G protein-coupled receptor kinase 5 (GRK5) is an important mediator of cardiovascular homeostasis through dampening of GPCR signaling, and is expressed in the heart and up-regulated in human HF. Of note, GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes in a calcium-calmodulin (Ca2+-CAM)-dependent manner, promoting hypertrophic gene transcription through activation of nuclear factor of activated T cells (NFAT). Interestingly, NFAT is also involved in fibroblast activation. GRK5 is highly expressed and active in cardiac fibroblasts; however, its pathophysiological role in these crucial cardiac cells is unknown. We demonstrate using adult cardiac fibroblasts that genetic deletion of GRK5 inhibits angiotensin II (AngII)-mediated fibroblast activation. Fibroblast-specific deletion of GRK5 in mice led to decreased fibrosis and cardiac hypertrophy after chronic AngII infusion or after ischemic injury compared to nontransgenic littermate controls (NLCs). Mechanistically, we show that nuclear translocation of GRK5 is involved in fibroblast activation. These data demonstrate that GRK5 is a regulator of fibroblast activation in vitro and cardiac fibrosis in vivo. This adds to previously published data which demonstrate the potential beneficial effects of GRK5 inhibition in the context of cardiac disease.
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Affiliation(s)
- Akito Eguchi
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - Ryan Coleman
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - Kenneth Gresham
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - Erhe Gao
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - Jessica Ibetti
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - J Kurt Chuprun
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
| | - Walter J Koch
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140;
- Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140
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Shin YJ, Shafranek RT, Tsui JH, Walcott J, Nelson A, Kim DH. 3D bioprinting of mechanically tuned bioinks derived from cardiac decellularized extracellular matrix. Acta Biomater 2021; 119:75-88. [PMID: 33166713 DOI: 10.1016/j.actbio.2020.11.006] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022]
Abstract
3D bioprinting is a powerful technique for engineering tissues used to study cell behavior and tissue properties in vitro. With the right formulation and printing parameters, bioinks can provide native biological and mechanical cues while allowing for versatile 3D structures that recapitulate tissue-level organization. Bio-based materials that support cellular adhesion, differentiation, and proliferation - including gelatin, collagen, hyaluronic acid, and alginate - have been successfully used as bioinks. In particular, decellularized extracellular matrix (dECM) has become a promising material with the unique ability to maintain both biochemical and topographical micro-environments of native tissues. However, dECM has shown technical limitations for 3D printing (3DP) applications posed by its intrinsically low mechanical stability. Herein, we report hydrogel bioinks composed of partially digested, porcine cardiac decellularized extracellular matrix (cdECM), Laponite-XLG nanoclay, and poly(ethylene glycol)-diacrylate (PEG-DA). The Laponite facilitated extrusion-based 3DP, while PEG-DA enabled photo-polymerization after printing. Improving upon previously reported bioinks derived from dECM, our bioinks combine extrudability, shape fidelity, rapid cross-linking, and cytocompatibility in a single formulation (> 97% viability of encapsulated human cardiac fibroblasts and > 94% viability of human induced pluripotent stem cell derived cardiomyocytes after 7 days). The compressive modulus of the cured hydrogel bioinks was tunable from 13.4-89 kPa by changing the concentration of PEG-DA in the bioink formulation. Importantly, this span of mechanical stiffness encompasses ranges of tissue stiffness from healthy (compressive modulus ~5-15 kPa) to fibrotic (compressive modulus ~30-100 kPa) cardiac tissue states. The printed constructs demonstrated shape fidelity, adaptability to different printing conditions, and high cell viability following extrusion and photo-polymerization, highlighting the potential for applications in modeling both healthy and fibrotic cardiac tissue.
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