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Teuwen JTJ, van der Vorst EPC, Maas SL. Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis. Int J Mol Sci 2024; 25:6213. [PMID: 38892400 PMCID: PMC11172518 DOI: 10.3390/ijms25116213] [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: 04/13/2024] [Revised: 05/30/2024] [Accepted: 06/02/2024] [Indexed: 06/21/2024] Open
Abstract
Circulating low-density lipoprotein (LDL) levels are a major risk factor for cardiovascular diseases (CVD), and even though current treatment strategies focusing on lowering lipid levels are effective, CVD remains the primary cause of death worldwide. Atherosclerosis is the major cause of CVD and is a chronic inflammatory condition in which various cell types and protein kinases play a crucial role. However, the underlying mechanisms of atherosclerosis are not entirely understood yet. Notably, protein kinases are highly druggable targets and represent, therefore, a novel way to target atherosclerosis. In this review, the potential role of the calcium/calmodulin-dependent protein kinase-like (CaMKL) family and its role in atherosclerosis will be discussed. This family consists of 12 subfamilies, among which are the well-described and conserved liver kinase B1 (LKB1) and 5' adenosine monophosphate-activated protein kinase (AMPK) subfamilies. Interestingly, LKB1 plays a key role and is considered a master kinase within the CaMKL family. It has been shown that LKB1 signaling leads to atheroprotective effects, while, for example, members of the microtubule affinity-regulating kinase (MARK) subfamily have been described to aggravate atherosclerosis development. These observations highlight the importance of studying kinases and their signaling pathways in atherosclerosis, bringing us a step closer to unraveling the underlying mechanisms of atherosclerosis.
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Affiliation(s)
- Jules T. J. Teuwen
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 München, Germany
| | - Sanne L. Maas
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
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De Meyer GRY, Zurek M, Puylaert P, Martinet W. Programmed death of macrophages in atherosclerosis: mechanisms and therapeutic targets. Nat Rev Cardiol 2024; 21:312-325. [PMID: 38163815 DOI: 10.1038/s41569-023-00957-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2023] [Indexed: 01/03/2024]
Abstract
Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis - the efficient clearance of dead cells by macrophages - is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies.
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Affiliation(s)
- Guido R Y De Meyer
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
| | - Michelle Zurek
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Pauline Puylaert
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
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3
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Woźniak E, Broncel M, Woźniak A, Satała J, Pawlos A, Bukowska B, Gorzelak-Pabiś P. Lipoprotein(a) is associated with DNA damage in patients with heterozygous familial hypercholesterolemia. Sci Rep 2024; 14:2564. [PMID: 38297066 PMCID: PMC10830471 DOI: 10.1038/s41598-024-52571-w] [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: 12/15/2023] [Accepted: 01/20/2024] [Indexed: 02/02/2024] Open
Abstract
Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients.
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Affiliation(s)
- Ewelina Woźniak
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland.
| | - Marlena Broncel
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Agnieszka Woźniak
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Joanna Satała
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Agnieszka Pawlos
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
| | - Bożena Bukowska
- Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Paulina Gorzelak-Pabiś
- Laboratory of Tissue Immunopharmacology, Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland
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Marin E, Lanzutti A. Biomedical Applications of Titanium Alloys: A Comprehensive Review. MATERIALS (BASEL, SWITZERLAND) 2023; 17:114. [PMID: 38203968 PMCID: PMC10780041 DOI: 10.3390/ma17010114] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024]
Abstract
Titanium alloys have emerged as the most successful metallic material to ever be applied in the field of biomedical engineering. This comprehensive review covers the history of titanium in medicine, the properties of titanium and its alloys, the production technologies used to produce biomedical implants, and the most common uses for titanium and its alloys, ranging from orthopedic implants to dental prosthetics and cardiovascular devices. At the core of this success lies the combination of machinability, mechanical strength, biocompatibility, and corrosion resistance. This unique combination of useful traits has positioned titanium alloys as an indispensable material for biomedical engineering applications, enabling safer, more durable, and more efficient treatments for patients affected by various kinds of pathologies. This review takes an in-depth journey into the inherent properties that define titanium alloys and which of them are advantageous for biomedical use. It explores their production techniques and the fabrication methodologies that are utilized to machine them into their final shape. The biomedical applications of titanium alloys are then categorized and described in detail, focusing on which specific advantages titanium alloys are present when compared to other materials. This review not only captures the current state of the art, but also explores the future possibilities and limitations of titanium alloys applied in the biomedical field.
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Affiliation(s)
- Elia Marin
- Ceramic Physics Laboratory, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan
- Department of Dental Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Department Polytechnic of Engineering and Architecture, University of Udine, 33100 Udine, Italy
- Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan
| | - Alex Lanzutti
- Department Polytechnic of Engineering and Architecture, University of Udine, 33100 Udine, Italy
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Huangfu N, Ma H, Tian M, Zhang J, Wang Y, Li Z, Chen X, Cui H. DHX9 Strengthens Atherosclerosis Progression By Promoting Inflammation in Macrophages. Inflammation 2023; 46:1725-1738. [PMID: 37326773 PMCID: PMC10567826 DOI: 10.1007/s10753-023-01836-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/26/2023] [Accepted: 05/11/2023] [Indexed: 06/17/2023]
Abstract
Atherosclerosis (AS) is the main cause of cerebrovascular diseases, and macrophages play important roles in atherosclerosis. DExH-Box helicase 9 (DHX9), as a member of DExD/H-box RNA helicase superfamily II, is identified as an autoantigen in the sera of systemic lupus erythematosus patients to trigger inflammation. The aim of this study was to investigate whether DHX9 is involved in AS development, especially in macrophages-mediated-inflammatory responses. We find that DHX9 expression is significantly increased in oxLDL or interferon-γ-treated macrophages and peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Knockdown of DHX9 inhibits lipid uptake and pro-inflammatory factors expression in macrophages, and ameliorates TNF-α-mediated monocyte adhesion capacity. Furthermore, we find that oxLDL stimulation promotes DHX9 interaction with p65 in macrophages, and further enhances the transcriptional activity of DHX9-p65-RNA Polymerase II complex to produce inflammatory factors. Moreover, using ApoE -/- mice fed with western diet to establish AS model, we find that knockdown of DHX9 mediated by adeno-associated virus-Sh-DHX9 through tail vein injection evidently alleviates AS progression in vivo. Finally, we also find that knockdown of DHX9 inhibits p65 activation, inflammatory factors expression, and the transcriptional activity of p65-RNA Polymerase II complex in PBMCs from patients with CAD. Overall, these results indicate that DHX9 promotes AS progression by enhancing inflammation in macrophages, and suggest DHX9 as a potential target for developing therapeutic drug.
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Affiliation(s)
- Ning Huangfu
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China
| | - Hongchuang Ma
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China
| | - Mengyun Tian
- School of Medicine, Ningbo University, Ningbo, 315000, China
| | - Jie Zhang
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- School of Medicine, Ningbo University, Ningbo, 315000, China
| | - Yong Wang
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China
| | - Zhenwei Li
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China
| | - Xiaomin Chen
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China.
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China.
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China.
| | - Hanbin Cui
- Department of Cardiology, Ningbo First Hospital, Ningbo, 315000, China.
- Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo, 315000, China.
- Clinical Medicine Research Centre for Cardiovascular Disease of Ningbo, Ningbo, 315000, China.
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Nguyen MTH, Imanishi M, Li S, Chau K, Banerjee P, Velatooru LR, Ko KA, Samanthapudi VSK, Gi YJ, Lee LL, Abe RJ, McBeath E, Deswal A, Lin SH, Palaskas NL, Dantzer R, Fujiwara K, Borchrdt MK, Turcios EB, Olmsted-Davis EA, Kotla S, Cooke JP, Wang G, Abe JI, Le NT. Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition. Front Cardiovasc Med 2023; 10:1187490. [PMID: 37711550 PMCID: PMC10499395 DOI: 10.3389/fcvm.2023.1187490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/24/2023] [Indexed: 09/16/2023] Open
Abstract
Background The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. Method We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation. Result Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS). Summary In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.
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Affiliation(s)
- Minh T. H. Nguyen
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
- Department of Life Science, Vietnam Academy of Science and Technology, University of Science and Technology of Hanoi, Hanoi, Vietnam
| | - Masaki Imanishi
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shengyu Li
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Khanh Chau
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Priyanka Banerjee
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Loka reddy Velatooru
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Kyung Ae Ko
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | | | - Young J. Gi
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Ling-Ling Lee
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rei J. Abe
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Elena McBeath
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anita Deswal
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Steven H. Lin
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nicolas L. Palaskas
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Dantzer
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Keigi Fujiwara
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mae K. Borchrdt
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Estefani Berrios Turcios
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - John P. Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nhat-Tu Le
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
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Banerjee P, Rosales JE, Chau K, Nguyen MTH, Kotla S, Lin SH, Deswal A, Dantzer R, Olmsted-Davis EA, Nguyen H, Wang G, Cooke JP, Abe JI, Le NT. Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors. Front Cardiovasc Med 2023; 10:1186679. [PMID: 37332576 PMCID: PMC10272458 DOI: 10.3389/fcvm.2023.1186679] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023] Open
Abstract
Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.
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Affiliation(s)
- Priyanka Banerjee
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Julia Enterría Rosales
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- School of Medicine, Instituto Tecnológico de Monterrey, Guadalajara, Mexico
| | - Khanh Chau
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Minh T. H. Nguyen
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
- Department of Life Science, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Steven H. Lin
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anita Deswal
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Dantzer
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Hung Nguyen
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - John P. Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nhat-Tu Le
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
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Nikpay M. Genome-wide search identified DNA methylation sites that regulate the metabolome. Front Genet 2023; 14:1093882. [PMID: 37274792 PMCID: PMC10233745 DOI: 10.3389/fgene.2023.1093882] [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: 11/09/2022] [Accepted: 05/09/2023] [Indexed: 06/07/2023] Open
Abstract
Background: Identifying DNA methylation sites that regulate the metabolome is important for several purposes. In this study, publicly available GWAS data were integrated to find methylation sites that impact metabolome through a discovery and replication scheme and by using Mendelian randomization. Results: The outcome of analyses revealed 107 methylation sites associated with 84 metabolites at the genome-wide significance level (p<5e-8) at both the discovery and replication stages. A large percentage of the observed associations (85%) were with lipids, significantly higher than expected (p = 0.0003). A number of CpG (methylation) sites showed specificity e.g., cg20133200 within PFKP was associated with glucose only and cg10760299 within GATM impacted the level of creatinine; in contrast, there were sites associated with numerous metabolites e.g., cg20102877 on the 2p23.3 region was associated with 39 metabolites. Integrating transcriptome data enabled identifying genes (N = 82) mediating the impact of methylation sites on the metabolome and cardiometabolic traits. For example, PABPC4 mediated the impact of cg15123755-HDL on type-2 diabetes. KCNK7 mediated the impact of cg21033440-lipids on hypertension. POC5, ILRUN, FDFT1, and NEIL2 mediated the impact of CpG sites on obesity through metabolic pathways. Conclusion: This study provides a catalog of DNA methylation sites that regulate the metabolome for downstream applications.
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9
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Sukhanov S, Higashi Y, Yoshida T, Danchuk S, Alfortish M, Goodchild T, Scarborough A, Sharp T, Jenkins JS, Garcia D, Ivey J, Tharp DL, Schumacher J, Rozenbaum Z, Kolls JK, Bowles D, Lefer D, Delafontaine P. Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia. JCI Insight 2023; 8:e165713. [PMID: 36602878 PMCID: PMC9990768 DOI: 10.1172/jci.insight.165713] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.
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Affiliation(s)
- Sergiy Sukhanov
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Yusuke Higashi
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Tadashi Yoshida
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Svitlana Danchuk
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Mitzi Alfortish
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Traci Goodchild
- Cardiovascular Center of Excellence, School of Medicine, Louisiana State University, New Orleans, Louisiana, USA
| | - Amy Scarborough
- Cardiovascular Center of Excellence, School of Medicine, Louisiana State University, New Orleans, Louisiana, USA
| | - Thomas Sharp
- Cardiovascular Center of Excellence, School of Medicine, Louisiana State University, New Orleans, Louisiana, USA
| | | | | | - Jan Ivey
- Ochsner Medical Center, New Orleans, Louisiana, USA
| | - Darla L. Tharp
- Department of Biomedical Sciences, University of Missouri-Columbia, Missouri, USA
| | - Jeffrey Schumacher
- Cardiovascular Center of Excellence, School of Medicine, Louisiana State University, New Orleans, Louisiana, USA
| | - Zach Rozenbaum
- Tulane University School of Medicine, New Orleans, Louisiana, USA
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Jay K. Kolls
- Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Douglas Bowles
- Department of Biomedical Sciences, University of Missouri-Columbia, Missouri, USA
| | - David Lefer
- Cardiovascular Center of Excellence, School of Medicine, Louisiana State University, New Orleans, Louisiana, USA
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10
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Ahmad S, Tan M, Hamid S. DNA repair mechanisms: Exploring potentials of nutraceutical. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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11
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Nikfarjam S, Singh KK. DNA damage response signaling: A common link between cancer and cardiovascular diseases. Cancer Med 2023; 12:4380-4404. [PMID: 36156462 PMCID: PMC9972122 DOI: 10.1002/cam4.5274] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/10/2022] [Accepted: 07/19/2022] [Indexed: 11/10/2022] Open
Abstract
DNA damage response (DDR) signaling ensures genomic and proteomic homeostasis to maintain a healthy genome. Dysregulation either in the form of down- or upregulation in the DDR pathways correlates with various pathophysiological states, including cancer and cardiovascular diseases (CVDs). Impaired DDR is studied as a signature mechanism for cancer; however, it also plays a role in ischemia-reperfusion injury (IRI), inflammation, cardiovascular function, and aging, demonstrating a complex and intriguing relationship between cancer and pathophysiology of CVDs. Accordingly, there are increasing number of reports indicating higher incidences of CVDs in cancer patients. In the present review, we thoroughly discuss (1) different DDR pathways, (2) the functional cross talk among different DDR mechanisms, (3) the role of DDR in cancer, (4) the commonalities and differences of DDR between cancer and CVDs, (5) the role of DDR in pathophysiology of CVDs, (6) interventional strategies for targeting genomic instability in CVDs, and (7) future perspective.
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Affiliation(s)
- Sepideh Nikfarjam
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.,Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Krishna K Singh
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.,Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
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12
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Zhang G, Liu Z, Deng J, Liu L, Li Y, Weng S, Guo C, Zhou Z, Zhang L, Wang X, Liu G, Guo J, Bai J, Wang Y, Du Y, Li TS, Tang J, Zhang J. Smooth muscle cell fate decisions decipher a high-resolution heterogeneity within atherosclerosis molecular subtypes. J Transl Med 2022; 20:568. [PMID: 36474294 PMCID: PMC9724432 DOI: 10.1186/s12967-022-03795-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis. METHODS The dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded. RESULTS We proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment. CONCLUSIONS This study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.
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Affiliation(s)
- Ge Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Zaoqu Liu
- grid.412633.10000 0004 1799 0733Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jinhai Deng
- grid.13097.3c0000 0001 2322 6764Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King’s College London, London, UK
| | - Long Liu
- grid.412633.10000 0004 1799 0733Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yu Li
- grid.260463.50000 0001 2182 8825Medical College, Nanchang University, Nanchang, 330006 Jiangxi China
| | - Siyuan Weng
- grid.412633.10000 0004 1799 0733Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Chunguang Guo
- grid.412633.10000 0004 1799 0733Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Zhaokai Zhou
- grid.412633.10000 0004 1799 0733Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Li Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Xiaofang Wang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Gangqiong Liu
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jiacheng Guo
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jing Bai
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Yunzhe Wang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Youyou Du
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Tao-Sheng Li
- grid.174567.60000 0000 8902 2273Department of Stem Cell Biology, Atomic Bomb Diseases Institute, Nagasaki University, Nagasaki, 852-8523 Japan
| | - Junnan Tang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
| | - Jinying Zhang
- grid.412633.10000 0004 1799 0733Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052 Henan China ,Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052 Henan China ,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052 Henan China
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13
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Rostami A, Vakili S, Koohpeyma F, Jahromi BN, Aghajari ZA, Mahmoudikohani F, Saki F, Mahmoodi M, Jaberi KR, Movahedpour A, Khorchani MJ, Noroozi S. Ellagic acid effects on testis, sex hormones, oxidative stress, and apoptosis in the relative sterility rat model following busulfan administration. BMC Complement Med Ther 2022; 22:170. [PMID: 35739528 PMCID: PMC9229441 DOI: 10.1186/s12906-022-03650-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Busulfan is an antineoplastic medication that is broadly utilized for cancer treatment. It affects the testicular function and leads to sterility. The present study aimed to evaluate the effects of ellagic acid on testicular tissue changes, sexual hormones, antioxidant defense system, and caspase-9 and Bcl2 gene expression in the busulfan-induced relative sterile rat model. METHODS This is an interventional-experimental animal study that was performed on 65 Adult male rats; they were randomly divided into five groups including control (1 ml of 0.9% normal saline), ellagic acid (50 mg/kg); busulfan (10 mg/kg); and busulfan plus ellagic acid (10 mg/kg and 50 mg/kg). At the end of the experiment, blood samples were collected, and plasma levels of sex hormones, antioxidant system, apoptosis-related genes, and testis histology were assessed. RESULTS Busulfan reduced the levels of serum testosterone, total antioxidant capacity, gene expression of Bcl2, testicular volume, seminiferous tubule, germinal epithelium, interstitial tissue volume, and the number of spermatogonia, spermatocyte, round spermatid, elongated spermatid, Sertoli cells and Leydig cells (p < 0.05). Busulfan administration resulted in a significant increase (p < 0.05) in the level of LH, FSH, malondialdehyde, and caspase 9. Busulfan + ellagic acid (50 mg/kg) showed higher serum levels of testosterone, gene expression of Bcl-2 and antioxidant markers, and lower LH, FSH levels, and gene expression of caspase 9 compared to the Busulfan-treated rats (p < 0.05). Stereological parameters were also ameliorated in the group treated with Busulfan+ 50 mg/kg ellagic acid (p < 0.05). CONCLUSION In conclusion, the consumption of ellagic acid may have beneficial effects on the antioxidant defense system, sexual hormone abnormality, and testicular tissue damage induced by busulfan.
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Affiliation(s)
- Amirabbas Rostami
- Department of Internal Medicine, Faculty of General Medicine, Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia
| | - Sina Vakili
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farhad Koohpeyma
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahia Namavar Jahromi
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Fatemeh Mahmoudikohani
- Department of Midwifery, School of Nursing and Midwifery, Bam University of Medical Sciences, Bam, Iran
| | - Forough Saki
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marzieh Mahmoodi
- School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khojaste Rahimi Jaberi
- Shiraz nephro-urology research center, shiraz university of medical sciences, Shiraz, Iran
| | | | | | - Saam Noroozi
- Department of Biochemistry, Fasa University of Medical Sciences, Fasa, Iran.
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14
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Ravi S, Duraisamy P, Krishnan M, Martin LC, Manikandan B, Raman T, Sundaram J, Arumugam M, Ramar M. An insight on 7- ketocholesterol mediated inflammation in atherosclerosis and potential therapeutics. Steroids 2021; 172:108854. [PMID: 33930389 DOI: 10.1016/j.steroids.2021.108854] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 11/24/2022]
Abstract
7-ketocholesterol, a toxic oxidative product of oxysterol is a causative agent of several diseases and disabilities concomitant to aging including cardiovascular diseases like atherosclerosis. Auto-oxidation of cholesterol esters present in low-density lipoprotein (LDL) deposits lead to the formation of oxidized LDL (Ox-LDL) along with its byproducts, namely 7KCh. It is predominantly found in atherosclerotic plaque and also found to be more atherogenic than cholesterol by being cytotoxic, interfering with cellular homeostasis. This makes it a serious threat by being the foremost cause of morbidity and mortality worldwide and is likely to become more serious during forth coming years. It involves in mediating inflammatory mechanisms characterized by the advancement of fibroatheroma plaques. The atherosclerotic lesion is composed of Ox-LDL along with fibrotic mass consisting of immune cells and molecules. Macrophages being the specialized phagocytic cells, contribute to removal of detrimental contents of the lesion along with accumulated lipids leading to alteration of its biology and functionality due to its plasticity. Here, we have explored the known as well as proposed mechanisms involved with 7KCh associated atherogenesis along with potential therapeutic strategies for targeting 7KCh as a diagnostic and target in medicine.
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Affiliation(s)
- Sangeetha Ravi
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
| | | | - Mahalakshmi Krishnan
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
| | - Livya C Martin
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
| | - Beulaja Manikandan
- Department of Biochemistry, Annai Veilakanni's College for Women, Chennai 600015, India
| | - Thiagarajan Raman
- Department of Advanced Zoology and Biotechnology, Ramakrishna Mission Vivekananda College, Mylapore, Chennai 600004, India
| | - Janarthanan Sundaram
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
| | - Munusamy Arumugam
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India
| | - Manikandan Ramar
- Department of Zoology, University of Madras, Guindy Campus, Chennai 600 025, India.
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15
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Haemmig S, Yang D, Sun X, Das D, Ghaffari S, Molinaro R, Chen L, Deng Y, Freeman D, Moullan N, Tesmenitsky Y, Wara AKMK, Simion V, Shvartz E, Lee JF, Yang T, Sukova G, Marto JA, Stone PH, Lee WL, Auwerx J, Libby P, Feinberg MW. Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence. Sci Transl Med 2021; 12:12/531/eaaw1868. [PMID: 32075942 DOI: 10.1126/scitranslmed.aaw1868] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 08/27/2019] [Accepted: 01/10/2020] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr -/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr -/- mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.
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Affiliation(s)
- Stefan Haemmig
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dafeng Yang
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Cardiology, Xiangya Hospital, Central South University, 0731 Changsha, Hunan, China
| | - Xinghui Sun
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Debapria Das
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Siavash Ghaffari
- Keenan Research Centre, St. Michael's Hospital and Department of Biochemistry, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Roberto Molinaro
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,School of Pharmacy, Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Lei Chen
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Cardiology, Xiangya Hospital, Central South University, 0731 Changsha, Hunan, China
| | - Yihuan Deng
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dan Freeman
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Norman Moullan
- Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Yevgenia Tesmenitsky
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - A K M Khyrul Wara
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Viorel Simion
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Eugenia Shvartz
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - James F Lee
- The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Tianlun Yang
- Department of Cardiology, Xiangya Hospital, Central South University, 0731 Changsha, Hunan, China
| | - Galina Sukova
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jarrod A Marto
- The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.,Departments of Cancer Biology and Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.,Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Peter H Stone
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Warren L Lee
- Keenan Research Centre, St. Michael's Hospital and Department of Biochemistry, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Peter Libby
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Mark W Feinberg
- Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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16
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Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits. Life Sci 2021; 272:119240. [PMID: 33600862 DOI: 10.1016/j.lfs.2021.119240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 01/05/2023]
Abstract
AIMS The mechanisms of atrial fibrillation (AF) in diabetes mellitus (DM) involve a complex interplay between increased oxidative stress, mitochondrial dysfunction and atrial remodeling. In this study, we examined the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial oxidative stress and atrial remodeling in a rabbit model of diabetes mellitus (DM). MAIN METHODS Healthy rabbits were selected and randomly divided into control, diabetic and apocynin administration group. Parameters of echocardiography, atrial electrophysiology, oxidative stress and mitochondrial function were compared between the different groups. KEY FINDINGS Compared to the control group, the DM group showed higher activity of NADPH oxidase, increased oxidative stress, larger left atrial diameter, a reduction in atrial mean conduction velocity. These findings were associated with increased interstitial fibrosis of the atria and higher atrial fibrillation (AF) inducibility. Moreover, atrial ultrastructure and mitochondrial function such as the mitochondrial respiratory control rate (RCR) were impaired. NADPH oxidase inhibition using the pharmacological agent apocynin improved these changes. SIGNIFICANCE NADPH oxidase activity plays an important role in mitochondrial oxidative stress, which is associated with AF inducibility by promoting adverse atrial remodeling. The NADPH oxidase inhibitor apocynin can prevent these pathological changes and may be a potential drug for AF treatment.
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17
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Møller P, Stopper H, Collins AR. Measurement of DNA damage with the comet assay in high-prevalence diseases: current status and future directions. Mutagenesis 2021; 35:5-18. [PMID: 31294794 DOI: 10.1093/mutage/gez018] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 06/19/2019] [Indexed: 12/12/2022] Open
Abstract
The comet assay is widely used in studies on genotoxicity testing, human biomonitoring and clinical studies. The simple version of the assay detects a mixture of DNA strand breaks and alkali-labile sites; these lesions are typically described as DNA strand breaks to distinguish them from oxidatively damaged DNA that are measured with the enzyme-modified comet assay. This review assesses the association between high-prevalence diseases in high-income countries and DNA damage measured with the comet assay in humans. The majority of case-control studies have assessed genotoxicity in white blood cells. Patients with coronary artery disease, diabetes, kidney disease, chronic obstructive pulmonary disease and Alzheimer's disease have on average 2-fold higher levels of DNA strand breaks compared with healthy controls. Patients with coronary artery disease, diabetes, kidney disease and chronic obstructive pulmonary disease also have 2- to 3-fold higher levels of oxidatively damaged DNA in white blood cells than controls, although there is not a clear difference in DNA damage levels between the different diseases. Case-control studies have shown elevated levels of DNA strand breaks in patients with breast cancer, whereas there are only few studies on colorectal and lung cancers. At present, it is not possible to assess if these neoplastic diseases are associated with a different level of DNA damage compared with non-neoplastic diseases.
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Affiliation(s)
- Peter Møller
- Department of Public Health, Section of Environmental Health, University of Copenhagen, Copenhagen H, Denmark
| | - Helga Stopper
- Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Germany
| | - Andrew R Collins
- Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway
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18
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Cioffi F, Adam RHI, Broersen K. Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer's Disease. J Alzheimers Dis 2020; 72:981-1017. [PMID: 31744008 PMCID: PMC6971833 DOI: 10.3233/jad-190863] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Alzheimer’s disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-β deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer’s disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer’s disease-related oxidative stress.
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Affiliation(s)
- Federica Cioffi
- Nanobiophysics Group, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Rayan Hassan Ibrahim Adam
- Nanobiophysics Group, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Kerensa Broersen
- Applied Stem Cell Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
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19
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Zhang X, Li L. The Significance of 8-oxoGsn in Aging-Related Diseases. Aging Dis 2020; 11:1329-1338. [PMID: 33014540 PMCID: PMC7505272 DOI: 10.14336/ad.2019.1021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/21/2019] [Indexed: 01/10/2023] Open
Abstract
Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.
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Affiliation(s)
- Xinmu Zhang
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Lin Li
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
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Li Z, Chen X, Liu Z, Ye W, Li L, Qian L, Ding H, Li P, Aung LHH. Recent Advances: Molecular Mechanism of RNA Oxidation and Its Role in Various Diseases. Front Mol Biosci 2020; 7:184. [PMID: 32850971 PMCID: PMC7413073 DOI: 10.3389/fmolb.2020.00184] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022] Open
Abstract
Compared with the research on DNA damage, there are fewer studies on RNA damage, and the damage mechanism remains mostly unknown. Recent studies have shown that RNA is more vulnerable to damage than DNA when the cells are exposed to endogenous and exogenous insults. RNA injury may participate in a variety of disease occurrence and development. RNA not only has important catalytic functions and other housekeeping functions, it also plays a decisive role in the translation of genetic information and protein biosynthesis. Various kinds of stressors, such as ultraviolet, reactive oxygen species and nitrogen, can cause damage to RNA. It may involve in the development and progression of diseases. In this review, we focused on the relationship between the RNA damage and disease as well as the research progress on the mechanism of RNA damage, which is of great significance for the pathogenesis, diagnosis, and treatment of related diseases.
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Affiliation(s)
- Zhe Li
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.,School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiatian Chen
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.,School of Basic Medicine, Qingdao University, Qingdao, China
| | - Ziqian Liu
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.,School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wei Ye
- Jiangsu Provincial Engineering Research Center for Biomedical Materials and Advanced Medical Device, Huaiyin Institute of Technology, Huaian, China
| | - Ling Li
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Lili Qian
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Hongyan Ding
- Jiangsu Provincial Engineering Research Center for Biomedical Materials and Advanced Medical Device, Huaiyin Institute of Technology, Huaian, China
| | - Peifeng Li
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Lynn Htet Htet Aung
- Center for Molecular Genetics, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.,School of Basic Medicine, Qingdao University, Qingdao, China
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21
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Shah A, Gray K, Figg N, Finigan A, Starks L, Bennett M. Defective Base Excision Repair of Oxidative DNA Damage in Vascular Smooth Muscle Cells Promotes Atherosclerosis. Circulation 2019; 138:1446-1462. [PMID: 29643057 PMCID: PMC6053042 DOI: 10.1161/circulationaha.117.033249] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Supplemental Digital Content is available in the text. Background: Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown. Methods: We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE−/− mice. Results: Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species–induced regulation of OGG1 acetylation could be caused by reactive oxygen species–induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22α-OGG1 and SM22α-OGG1K-R mice) and crossed them with ApoE−/− mice. We also studied ApoE−/− mice deficient in OGG1 (OGG1−/−). OGG1−/− mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways. Conclusions: We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function.
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MESH Headings
- Acetylation
- Animals
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Biomarkers/metabolism
- Cells, Cultured
- DNA Damage
- DNA Glycosylases/deficiency
- DNA Glycosylases/genetics
- DNA Glycosylases/metabolism
- DNA Repair
- Disease Models, Animal
- Female
- Guanine/analogs & derivatives
- Guanine/metabolism
- Humans
- Male
- Mice, Knockout, ApoE
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Oxidative Stress
- Plaque, Atherosclerotic
- Protein Processing, Post-Translational
- Rats
- Sirtuin 1/genetics
- Sirtuin 1/metabolism
- p300-CBP Transcription Factors/metabolism
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Affiliation(s)
- Aarti Shah
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
| | - Kelly Gray
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
| | - Nichola Figg
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
| | - Alison Finigan
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
| | - Lakshi Starks
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
| | - Martin Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom
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Shah N, Meira LB, Elliott RM, Hoole SP, West NE, Brown AJ, Bennett MR, Garcia-Garcia HM, Kuku KO, Dan K, Kolm P, Mariathas M, Curzen N, Mahmoudi M. DNA Damage and Repair in Patients With Coronary Artery Disease: Correlation With Plaque Morphology Using Optical Coherence Tomography (DECODE Study). CARDIOVASCULAR REVASCULARIZATION MEDICINE 2019; 20:812-818. [DOI: 10.1016/j.carrev.2019.04.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 04/27/2019] [Accepted: 04/30/2019] [Indexed: 01/12/2023]
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23
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Inflammation and Vascular Ageing: From Telomeres to Novel Emerging Mechanisms. High Blood Press Cardiovasc Prev 2019; 26:321-329. [DOI: 10.1007/s40292-019-00331-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/12/2019] [Indexed: 12/20/2022] Open
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24
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Pescatore LA, Gamarra LF, Liberman M. Multifaceted Mechanisms of Vascular Calcification in Aging. Arterioscler Thromb Vasc Biol 2019; 39:1307-1316. [DOI: https:/doi.org/10.1161/atvbaha.118.311576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 05/12/2019] [Indexed: 08/30/2023]
Abstract
Approximately 20% of the world’s population will be around or above 65 years of age by the next decade. Out of these, 40% are suspected to have cardiovascular diseases as a cause of mortality. Arteriosclerosis, characterized by increased vascular calcification, impairing Windkessel effect and tissue perfusion, and determining end-organ damage, is a hallmark of vascular pathology in the elderly population. Risk factors accumulated during aging affect the normal physiological and vascular aging process, which contributes to the progression of arteriosclerosis. Traditional risk factors, age-associated diseases, and respective regulating mechanisms influencing vascular calcification and vascular stiffness have been extensively studied for many years. Despite the well-known fact that aging alone can induce vascular damage, specific mechanisms that implicate physiological aging in vascular calcification, contributing to vascular stiffness, are poorly understood. This review focuses on mechanisms activated during normal aging, for example, cellular senescence, autophagy, extracellular vesicles secretion, and oxidative stress, along with the convergence of premature aging models’ pathophysiology, such as Hutchinson-Gilford Progeria (prelamin accumulation) and Klotho deficiency, to understand vascular calcification in aging. Understanding the mechanisms of vascular damage in aging that intersect with age-associated diseases and risk factors is crucial to foster innovative therapeutic targets to mitigate cardiovascular disease.
Visual Overview—
An online visual overview is available for this article.
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Affiliation(s)
- Luciana A. Pescatore
- From the Hospital Israelita Albert Einstein, São Paulo, SP, Brazil (L.A.P., L.F.G., M.L.)
- Laboratório de Biologia Vascular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil (L.A.P.)
| | - Lionel F. Gamarra
- From the Hospital Israelita Albert Einstein, São Paulo, SP, Brazil (L.A.P., L.F.G., M.L.)
| | - Marcel Liberman
- From the Hospital Israelita Albert Einstein, São Paulo, SP, Brazil (L.A.P., L.F.G., M.L.)
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25
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Martinet W, Coornaert I, Puylaert P, De Meyer GRY. Macrophage Death as a Pharmacological Target in Atherosclerosis. Front Pharmacol 2019; 10:306. [PMID: 31019462 PMCID: PMC6458279 DOI: 10.3389/fphar.2019.00306] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 03/12/2019] [Indexed: 12/20/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disorder characterized by the gradual build-up of plaques within the vessel wall of middle-sized and large arteries. Over the past decades, treatment of atherosclerosis mainly focused on lowering lipid levels, which can be accomplished by the use of statins. However, some patients do not respond sufficiently to statin therapy and therefore still have a residual cardiovascular risk. This issue highlights the need for novel therapeutic strategies. As macrophages are implicated in all stages of atherosclerotic lesion development, they represent an important alternative drug target. A variety of anti-inflammatory strategies have recently emerged to treat or prevent atherosclerosis. Here, we review the canonical mechanisms of macrophage death and their impact on atherogenesis and plaque stability. Macrophage death is a prominent feature of advanced plaques and is a major contributor to necrotic core formation and plaque destabilization. Mechanisms of macrophage death in atherosclerosis include apoptosis, passive or accidental necrosis as well as secondary necrosis, a type of death that typically occurs when apoptotic cells are insufficiently cleared by neighboring cells via a phagocytic process termed efferocytosis. In addition, less-well characterized types of regulated necrosis in macrophages such as necroptosis, pyroptosis, ferroptosis, and parthanatos may occur in advanced plaques and are also discussed. Autophagy in plaque macrophages is an important survival pathway that protects against cell death, yet massive stimulation of autophagy promotes another type of death, usually referred to as autosis. Multiple lines of evidence indicate that a better insight into the different mechanisms of macrophage death, and how they mutually interact, will provide novel pharmacological strategies to resolve atherosclerosis and stabilize vulnerable, rupture-prone plaques.
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Affiliation(s)
- Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Isabelle Coornaert
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Pauline Puylaert
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Guido R Y De Meyer
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
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26
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Schwartz SM, Virmani R, Majesky MW. An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque? F1000Res 2018; 7:F1000 Faculty Rev-1969. [PMID: 30613386 PMCID: PMC6305222 DOI: 10.12688/f1000research.15994.1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2018] [Indexed: 12/13/2022] Open
Abstract
Almost 50 years ago, Earl Benditt and his son John described the clonality of the atherosclerotic plaque. This led Benditt to propose that the atherosclerotic lesion was a smooth muscle neoplasm, similar to the leiomyomata seen in the uterus of most women. Although the observation of clonality has been confirmed many times, interest in the idea that atherosclerosis might be a form of neoplasia waned because of the clinical success of treatments for hyperlipemia and because animal models have made great progress in understanding how lipid accumulates in the plaque and may lead to plaque rupture. Four advances have made it important to reconsider Benditt's observations. First, we now know that clonality is a property of normal tissue development. Second, this is even true in the vessel wall, where we now know that formation of clonal patches in that wall is part of the development of smooth muscle cells that make up the tunica media of arteries. Third, we know that the intima, the "soil" for development of the human atherosclerotic lesion, develops before the fatty lesions appear. Fourth, while the cells comprising this intima have been called "smooth muscle cells", we do not have a clear definition of cell type nor do we know if the initial accumulation is clonal. As a result, Benditt's hypothesis needs to be revisited in terms of changes in how we define smooth muscle cells and the quite distinct developmental origins of the cells that comprise the muscular coats of all arterial walls. Finally, since clonality of the lesions is real, the obvious questions are do these human tumors precede the development of atherosclerosis, how do the clones develop, what cell type gives rise to the clones, and in what ways do the clones provide the soil for development and natural history of atherosclerosis?
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Affiliation(s)
| | - Renu Virmani
- CV Path Institute, Gaithersberg, Maryland, 20878, USA
| | - Mark W. Majesky
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Hospital Research Institute, Seattle, WA, 98112, USA
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27
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Bhilare NV, Dhaneshwar SS, Mahadik KR. Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation. World J Hepatol 2018; 10:496-508. [PMID: 30079136 PMCID: PMC6068850 DOI: 10.4254/wjh.v10.i7.496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid (INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.
METHODS INH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.
RESULTS Prodrugs were found to be stable in acidic (pH 1.2) and basic (pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly (59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially.
CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.
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Affiliation(s)
- Neha Vithal Bhilare
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
| | - Suneela Sunil Dhaneshwar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
| | - Kakasaheb Ramoo Mahadik
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Maharashtra 411038, India
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Kamaletdinova TR, Rosenkranz AA, Ulasov AV, Khramtsov YV, Tsvetkova AD, Georgiev GP, Sobolev AS. Modular Nanotransporter with P21 Fragment Inhibits DNA Repair after Bleomycin Treatment. DOKL BIOCHEM BIOPHYS 2018; 479:95-97. [DOI: 10.1134/s1607672918020114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Indexed: 12/18/2022]
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Higashi T, Mai Y, Mazaki Y, Miwa S. Intracellular Ca 2+ is an essential factor for cell damage induced by unsaturated carbonyl compounds. J Biosci Bioeng 2017; 124:680-684. [PMID: 28751126 DOI: 10.1016/j.jbiosc.2017.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 06/21/2017] [Accepted: 07/07/2017] [Indexed: 01/09/2023]
Abstract
The unsaturated carbonyl compounds are known as the environmental pollutants. Acrolein (ACR) and methyl vinyl ketone (MVK) are representative unsaturated carbonyl compounds. ACR is contained in smoke, automobile exhaust, industrial waste, and several foods. MVK is widely used as the industrial chemical. Although ACR and MVK are highly toxic, the molecular mechanism for their cytotoxicity has been unclear. We have previously reported that ACR and MVK are major cytotoxic compounds in the gas phase of cigarette smoke, and protein kinase C (PKC) inhibitor and NADPH oxidases inhibitor partially rescued cells from ACR- or MVK-induced cell death (Noya et al., Toxicology, 314, 1-10, 2013). PKC translocation, which is hallmark for PKC activation, and cell damage were induced by treatment of cultured cells with ACR or MVK. Intracellular Ca2+ chelator completely suppressed ACR- or MVK-induced PKC translocation to the cell membrane and cell damage, while extracellular Ca2+ chelator had no effects on ACR- and MVK-induced cytotoxicity. These results suggest that intracellular Ca2+ is an essential factor for cell damage caused by both PKC-dependent and PKC-independent pathways, and mobilization of Ca2+ from intracellular Ca2+ stores is induced by ACR or MVK.
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Affiliation(s)
- Tsunehito Higashi
- Department of Cellular Pharmacology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
| | - Yosuke Mai
- Department of Cellular Pharmacology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Yuichi Mazaki
- Department of Cellular Pharmacology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
| | - Soichi Miwa
- Department of Cellular Pharmacology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan
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Abd El Aal HA, Ahmed LA, Hassan WA, Fawzy HM, Moawad H. Combination of carvacrol with simvastatin improves the lipid-lowering efficacy and alleviates simvastatin side effects. J Biochem Mol Toxicol 2017; 31. [PMID: 29071762 DOI: 10.1002/jbt.21981] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 08/13/2017] [Accepted: 08/19/2017] [Indexed: 01/08/2023]
Abstract
The present investigation was designed to examine the possible additive hypolipidemic effect of carvacrol (CARV) in combination with simvastatin (SIM) on poloxamer 407 (P407)-induced hyperlipidemia. Rats were injected with P407, (500 mg/ kg; i.p.), twice a week, for 30 days. Treatment was carried out by administration of SIM (20 mg/kg/day; p.o.) or CARV (50 mg/kg/day; p.o.) or combination of them. Treatment with CARV significantly decreased total cholesterol, triglycerides, low-density lipoprotein, atherogenic index, leptin, and increased high-density lipoprotein and adiponectin. Moreover, CARV potentiated the hypolipidemic effect of SIM. Both SIM and CARV alleviated the oxidative stress induced by P407. Interestingly, CARV, when combined with SIM, significantly ameliorated SIM-induced liver and muscle injury by reducing the level of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and myoglobin and restoring the normal histological picture of both liver and muscle as well as apoptosis.
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Affiliation(s)
- Hayat A Abd El Aal
- Department of Pharmacology, National Organization for Drug Control and Research, NODCAR, Giza, Egypt
| | - Lamiaa A Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Wedad A Hassan
- Department of Pharmacology, National Organization for Drug Control and Research, NODCAR, Giza, Egypt
| | - Hala M Fawzy
- Department of Pharmacology, National Organization for Drug Control and Research, NODCAR, Giza, Egypt
| | - Helmy Moawad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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31
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Mahadeva Rao US, Shanmuga Sundaram C. Antihypercholesterolemic, antioxidant and renal protective effects of Mengkudu (Rubiaceae) fruit in nephropathy-induced albino rats. Chin J Integr Med 2017:10.1007/s11655-017-2785-1. [PMID: 28914438 DOI: 10.1007/s11655-017-2785-1] [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: 02/12/2014] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To assess the modulatory impact of alcoholic extract of fruit of Mengkudu (AEFM, Morinda citrifolia L., Rubiaceae) on renal oxido-lipidemic stress in hypercholesterolemic albino rats. METHODS Twenty-four male albino rats were randomly divided into four groups with six rats in each group: group I as control, group II fed with hypercholesterolemic diet (HCD) for 45 days (4% cholesterol and 1% cholic acid), Group III rats fed with HCD for 45 days + AEFM (300 mg/kg body weight/day orally) for last 30 days and group IV normal rats fed AEFM alone. The blood was collected using ethylenediamine tetraacetic acid (EDTA) as an anticoagulant for various biochemical analysis, and excision of kidney was done for histological analysis. RESULTS The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters and lipid peroxidation products were markedly mitigated in AEFM treated hypercholesterolemic rats (group III) compared to group I (P<0.01). Activities of both enzymic and non-enzymic free radical scavenging factors were significantly increased in group III compared to group I (P<0.01). In group III the mRNA levels of interstitial endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) genes were obviously up-regulated (P<0.01) and down-regulated in (P<0.05) compared with group I. Histomorphological observations also exhibited similar as in group III AEFM commendably protects the renal tissues compared with group I (P<0.01). CONCLUSION AEFM can act as nephroprotective agent by attenuating the renal oxidative stress, lipid levels as well as regulating NOS level and by this means protects the kidney in hypercholesterolemic induced nephropathy experimental rats.
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Affiliation(s)
- U S Mahadeva Rao
- Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, 20400, Malaysia.
| | - C Shanmuga Sundaram
- Department of Microbiology, Hindustan College of arts and Science, Kelambakkam, Chennai, 603103, India
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32
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DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature. Eur J Pharmacol 2017; 816:116-128. [PMID: 28347738 DOI: 10.1016/j.ejphar.2017.03.050] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 03/07/2017] [Accepted: 03/23/2017] [Indexed: 12/15/2022]
Abstract
A decline in the function of the macro- and micro-vasculature occurs with ageing. DNA damage also accumulates with ageing, and thus DNA damage and repair have important roles in physiological ageing. Considerable evidence also supports a crucial role for DNA damage in the development and progression of macrovascular disease such as atherosclerosis. These findings support the concept that prolonged exposure to risk factors is a major stimulus for DNA damage within the vasculature, in part via the generation of reactive oxygen species. Genomic instability can directly affect vascular cellular function, leading to cell cycle arrest, apoptosis and premature vascular cell senescence. In contrast, the study of age-related impaired function and DNA damage mechanisms in the microvasculature is limited, although ageing is associated with microvessel endothelial dysfunction. This review examines current knowledge on the role of DNA damage and DNA repair systems in macrovascular disease such as atherosclerosis and microvascular disease. We also discuss the cellular responses to DNA damage to identify possible strategies for prevention and treatment.
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Deori M, Devi D, Kumari S, Hazarika A, Kalita H, Sarma R, Devi R. Antioxidant Effect of Sericin in Brain and Peripheral Tissues of Oxidative Stress Induced Hypercholesterolemic Rats. Front Pharmacol 2016; 7:319. [PMID: 27695419 PMCID: PMC5024675 DOI: 10.3389/fphar.2016.00319] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/02/2016] [Indexed: 01/22/2023] Open
Abstract
This study evaluated the antioxidant effect of crude sericin extract (CSE) from Antheraea assamensis in high cholesterol fed rats. Investigation was conducted by administering graded oral dose of 0.25 and 0.5 gm/kg body weight (b.w.)/day of CSE for a period of 28 days. Experiments were conducted in 30 rats and were divided into five groups: normal control, high cholesterol fed (HCF), HCF + 0.065 gm/kg b.w./day fenofibrate (FF), HCF + sericin 0.25 gm/kg b.w./day (LSD), and HCF + sericin 0.5 gm/kg b.w./day (HSD). In brain, heart, liver, serum, and kidney homogenates nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), superoxide dismutase, reduced glutathione (GSH) was measured. LSD treatment prevented the alterations in GSH and PCC levels in hypercholesterolemic (HyC) brain tissue homogenates of rats. CSE lowers the serum total cholesterol level in HyC rats by promoting fecal cholesterol (FC) excretion. CSE increases FC level by promoting inhibition of cholesterol absorption in intestine. The endogenous antioxidant reduced significantly and the oxidative stress marker TBARS level increases significantly in the peripheral tissue of HCF rats. However, the administration of LSD and HSD exhibited a good antioxidant activity by reducing the TBARS level and increasing the endogenous antioxidant in peripheral tissue. In addition, a histological examination revealed loss of normal liver and kidney architecture in cholesterol fed rats which were retained in sericin treated groups. The findings of this study suggested that CSE improves hypercholesterolemia in rats fed a HyC diet. Clinical relevance of this effect of CSE seems worthy of further studies.
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Affiliation(s)
- Meetali Deori
- Department of Zoology, Nalbari College Nalbari, India
| | - Dipali Devi
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Sima Kumari
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Ankita Hazarika
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Himadri Kalita
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Rahul Sarma
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
| | - Rajlakshmi Devi
- Life Sciences Division, Institute of Advanced Study in Science and Technology Guwahati, India
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Griendling KK, Touyz RM, Zweier JL, Dikalov S, Chilian W, Chen YR, Harrison DG, Bhatnagar A. Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association. Circ Res 2016; 119:e39-75. [PMID: 27418630 PMCID: PMC5446086 DOI: 10.1161/res.0000000000000110] [Citation(s) in RCA: 289] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.
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Zhang C, Luo T, Cui S, Gu Y, Bian C, Chen Y, Yu X, Wang Z. Poly(ADP-ribose) protects vascular smooth muscle cells from oxidative DNA damage. BMB Rep 2016; 48:354-9. [PMID: 25748172 PMCID: PMC4578623 DOI: 10.5483/bmbrep.2015.48.6.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Indexed: 11/20/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) undergo death during atherosclerosis, a
widespread cardiovascular disease. Recent studies suggest that oxidative damage
occurs in VSMCs and induces atherosclerosis. Here, we analyzed oxidative damage
repair in VSMCs and found that VSMCs are hypersensitive to oxidative damage.
Further analysis showed that oxidative damage repair in VSMCs is suppressed by a
low level of poly (ADP-ribosyl)ation (PARylation), a key post-translational
modification in oxidative damage repair. The low level of PARylation is not
caused by the lack of PARP-1, the major poly(ADP-ribose) polymerase activated by
oxidative damage. Instead, the expression of poly(ADP-ribose) glycohydrolase,
PARG, the enzyme hydrolyzing poly(ADP-ribose), is significantly higher in VSMCs
than that in the control cells. Using PARG inhibitor to suppress PARG activity
facilitates oxidative damage-induced PARylation as well as DNA damage repair.
Thus, our study demonstrates a novel molecular mechanism for oxidative
damage-induced VSMCs death. This study also identifies the use of PARG
inhibitors as a potential treatment for atherosclerosis. [BMB Reports 2015;
48(6): 354-359]
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Affiliation(s)
- Chao Zhang
- Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China
| | - Tao Luo
- Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China
| | - Shijun Cui
- Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China
| | - Yongquan Gu
- Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China
| | - Chunjing Bian
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Yibin Chen
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Xiaochun Yu
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Zhonggao Wang
- Vascular Surgery Department of Xuanwu Hospital, Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China
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Affiliation(s)
- Anna Uryga
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; ,
| | - Kelly Gray
- Cardiovascular Safety, AstraZeneca, Cambridge CB4 0FZ, United Kingdom;
| | - Martin Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; ,
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Zhao J, Zhang Q, Liu J, Tian L, Huang W, Quan J, Wang J, Xu Y, Wang Y, Niu R. Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms. J Diabetes Res 2016; 2016:9741483. [PMID: 27579327 PMCID: PMC4989076 DOI: 10.1155/2016/9741483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 02/16/2016] [Indexed: 12/28/2022] Open
Abstract
We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway.
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Affiliation(s)
- Juan Zhao
- Department of Endocrinology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Qi Zhang
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Jing Liu
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
- *Jing Liu:
| | - Liming Tian
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Wenhui Huang
- Department of Endocrinology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Jinxing Quan
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Jinyang Wang
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Yanjia Xu
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Yunfang Wang
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
| | - Ruilan Niu
- Department of Nephrology, Gansu Provincial Hospital, 204 West Donggang Road, Lanzhou, Gansu 730000, China
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Gong H, Li H, Zou J, Mi J, Liu F, Wang D, Yan D, Wang B, Zhang S, Tian G. The relationship between five non-synonymous polymorphisms within three XRCC genes and gastric cancer risk in a Han Chinese population. Tumour Biol 2015; 37:5905-10. [DOI: 10.1007/s13277-015-3502-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 04/23/2015] [Indexed: 12/14/2022] Open
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Grootaert MOJ, da Costa Martins PA, Bitsch N, Pintelon I, De Meyer GRY, Martinet W, Schrijvers DM. Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis. Autophagy 2015; 11:2014-2032. [PMID: 26391655 PMCID: PMC4824610 DOI: 10.1080/15548627.2015.1096485] [Citation(s) in RCA: 219] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 09/03/2015] [Accepted: 09/15/2015] [Indexed: 12/13/2022] Open
Abstract
Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7-/- VSMCs) caused accumulation of SQSTM1/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, CDKN2A-RB-mediated G1 proliferative arrest and senescence-associated GLB1 activity. Transfection of SQSTM1-encoding plasmid DNA in Atg7+/+ VSMCs induced similar features, suggesting that accumulation of SQSTM1 promotes VSMC senescence. Interestingly, atg7-/- VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor NFE2L2 resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of MMP9, TGFB and CXCL12 and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.
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Affiliation(s)
- Mandy OJ Grootaert
- Laboratory of Physiopharmacology; University of Antwerp; Antwerp, Belgium
| | - Paula A da Costa Martins
- Department of Cardiology; Cardiovascular Research Institute Maastricht; Maastricht, The Netherlands
| | - Nicole Bitsch
- Department of Cardiology; Cardiovascular Research Institute Maastricht; Maastricht, The Netherlands
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology; University of Antwerp; Antwerp, Belgium
| | - Guido RY De Meyer
- Laboratory of Physiopharmacology; University of Antwerp; Antwerp, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology; University of Antwerp; Antwerp, Belgium
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Uryga AK, Bennett MR. Ageing induced vascular smooth muscle cell senescence in atherosclerosis. J Physiol 2015; 594:2115-24. [PMID: 26174609 DOI: 10.1113/jp270923] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/08/2015] [Indexed: 12/16/2022] Open
Abstract
Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis.
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Affiliation(s)
- Anna K Uryga
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Box 110, Cambridge, CB2 0QQ, UK
| | - Martin R Bennett
- Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Box 110, Cambridge, CB2 0QQ, UK
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Baskaran UL, Sabina EP. The food supplement coenzyme Q10 and suppression of antitubercular drug-induced hepatic injury in rats: the role of antioxidant defence system, anti-inflammatory cytokine IL-10. Cell Biol Toxicol 2015; 31:211-9. [PMID: 26374116 DOI: 10.1007/s10565-015-9305-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 09/07/2015] [Indexed: 01/30/2023]
Abstract
INTRODUCTION Isoniazid (INH) and rifampicin (RIF), the most common anti-tubercular therapy, causes hepatotoxicity through a multi-step mechanism in certain individuals. The present study was an attempt to evaluate the hepatoprotective effect of coenzyme Q10 against INH + RIF-induced hepatotoxicity in Wistar albino rats. METHODS Hepatotoxicity was induced by the oral administration of INH + RIF (50 mg/kg b.w. each/day) in normal saline water for 28 days. The hepatoprotective effect of coenzyme Q10 (10 mg/kg b.w./day) was compared with that of the standard drug silymarin (25 mg/kg b.w./day). Animals were sacrificed at the end of the study period, and blood and liver were collected for biochemical, immunological and histological analyses. RESULTS Evaluation of biochemical parameters showed that coenzyme Q10 treatment caused significant (P < 0.05) reduction in the elevated levels of serum liver function markers and restored normal levels of total protein, albumin and lipids in INH + RIF-treated rats. Also, it was observed that coenzyme Q10 was able to restore normal levels of enzymic antioxidants, reduced glutathione and lipid peroxidation in the INH + RIF-treated rats. Coenzyme Q10 was found to effectively reduce the extent of liver damage caused due to INH + RIF. In addition, the levels of IL-10 and IL-6 were significantly elevated in the INH + RIF-induced rats treated with CoQ10. CONCLUSION Our study indicates the protective role of coenzyme Q10 in attenuating the hepatotoxic effects of INH + RIF in a rat model and that it could be used as a food supplement during anti-tubercular therapy.
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Affiliation(s)
| | - Evan Prince Sabina
- School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India.
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Abstract
Gray et al 1 describe studies to examine smooth muscle cell (SMC)-selective effects of acceleration or inhibition of double-strand DNA break repair on atherosclerotic lesion phenotype in the ApoE-/- mouse model. Markers of the DNA damage response (DDR) and expression of DNA repair enzymes are both significantly elevated in human atherosclerotic plaques as compared with non-atherosclerotic mammary arteries,2 and are also increased in experimental models of atherosclerosis, a process that can be reversed by dietary lipid lowering.3 The report by Gray et al 1 provides important insights into the specific contribution of SMCs to plaque phenotype when the DDR is manipulated in vivo . While complementary analyses of double-strand DNA break repair in other major cell types within atherosclerotic lesions are needed, data from the studies by Gray et al 1 suggest the possibility of harnessing atheroprotective features of the ataxia telangiectasia mutated (ATM) kinase,4 , 5 a primary initiator of the DDR.
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Affiliation(s)
- Babak Razani
- From the Cardiovascular Division, Departments of Medicine and Pathology/Immunology, Washington University School of Medicine, St. Louis, MO (B.R.); and Department of Pathology, University of Washington School of Medicine, Seattle (E.W.R.).
| | - Elaine W Raines
- From the Cardiovascular Division, Departments of Medicine and Pathology/Immunology, Washington University School of Medicine, St. Louis, MO (B.R.); and Department of Pathology, University of Washington School of Medicine, Seattle (E.W.R.).
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Tang L, Sakai Y, Ueda Y, Katsuda S. Effects of oral administration of tripeptides derived from type I collagen (collagen tripeptide) on atherosclerosis development in hypercholesterolemic rabbits. J Biosci Bioeng 2014; 119:558-63. [PMID: 25468425 DOI: 10.1016/j.jbiosc.2014.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 09/19/2014] [Accepted: 10/17/2014] [Indexed: 01/26/2023]
Abstract
Digestion of type I collagen with a collagenase-type protease yields a collagen tripeptide (Ctp) fraction comprising Gly-X-Y sequences that exhibit diverse biological activities. We previously demonstrated that Ctp inhibits the proliferation and migration of cultured aortic smooth muscle cells (SMCs) in vitro. These cells contribute to the pathogenesis of atherosclerosis and other cardiovascular diseases. In order to evaluate the effects of Ctp on atherosclerosis development in vivo, here we used the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit model of familial hypercholesterolemia to determine the effects of oral administration of Ctp for three months. Ctp induced a significant decrease in the area occupied by atherosclerotic plaques in the aorta and in the level of total serum cholesterol. The components of atherosclerotic plaques underwent distinct changes, including reduction in the populations of macrophages and SMCs and a significant decrease in the proportion of macrophages to SMCs. Ctp administration decreased the number of cells in plaques that expressed proliferating cell nuclear antigen and the number of cells with oxidative damage to DNA as indicated by 8-hydroxy-2'-deoxyguanine detection. These findings are the first to define the mechanism underlying the inhibitory effects of Ctp on atherosclerosis development in hypercholesterolemic rabbits, and suggest that Ctp provides an effective therapy for treating atherosclerosis.
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Affiliation(s)
- Lihua Tang
- Department of Pathophysiological and Experimental Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Yasuo Sakai
- Central Research Institute, Jellice Co., Ltd., 4-4-1 Sakae, Tagajo-shi, Miyagi 985-0833, Japan.
| | - Yoshimichi Ueda
- Department of Pathophysiological and Experimental Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
| | - Shogo Katsuda
- Department of Pathophysiological and Experimental Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan
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Subramanian M, Thorp E, Tabas I. Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling. Circ Res 2014; 116:e13-24. [PMID: 25348165 DOI: 10.1161/circresaha.116.304794] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
RATIONALE Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown. OBJECTIVE To understand the role of GM-CSF in advanced atherosclerotic plaque progression. METHODS AND RESULTS Ldlr(-/-) mice and Csf2(-/-)Ldlr(-/-) mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress. CONCLUSIONS In low-density lipoprotein-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23-inducing activity rather than its role as a growth factor.
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Affiliation(s)
- Manikandan Subramanian
- From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.)
| | - Edward Thorp
- From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.)
| | - Ira Tabas
- From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.).
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Kamesh V, Sumathi T. Nephroprotective potential of Bacopa monniera on hypercholesterolemia induced nephropathy via the NO signaling pathway. PHARMACEUTICAL BIOLOGY 2014; 52:1327-1334. [PMID: 25068673 DOI: 10.3109/13880209.2014.891142] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
CONTEXT Bacopa monniera L. (Scrophulariaceae) is used as a traditional medicine in India for various ailments such as epilepsy, mental disorders, and also as a cardio-tonic. However, its nephroprotective role is still unknown. OBJECTIVE The present study assesses the modulatory impact of the alcoholic (ethanol) extract of Bacopa monniera (AEBM) on renal oxido-lipidemic stress in hypercholesterolemic rats. MATERIALS AND METHODS B. monniera (1 kg) was extracted with 90% ethanol, filtered, and dried (52 g). Group-I rats as control, Group-II rats fed with a hypercholesterolemic diet (HCD) for 45 d [4% cholesterol and 1% cholic acid], Group-III rats fed with HCD for 45 d + AEBM (40 mg/kg, body weight) for last 30 d, and Group-IV AEBM alone rats. Blood and kidney were removed to analyze lipid, antioxidant status, and histological analysis. RESULT The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters (urea, creatinine, and uric acid), and lipid peroxidation (LPO) products were significantly attenuated (p < 0.01) in AEBM-treated hypercholesterolemic rats. Activities of both enzymic (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR)) and non-enzymic antioxidant (GSH, Vit-C, and Vit-E) were significantly increased (p < 0.01), on supplementation with AEBM. Administration with AEBM the mRNA levels of eNOS and iNOS genes was significantly up-regulated and down-regulated (p < 0.01). Histomorphological observations also evidenced that AEBM effectively protects the kidney from hypercholesterolemia-mediated oxido-lipidemic damage. DISCUSSION AND CONCLUSION From this study, we hypothesized that AEBM can act as renoprotective agent by attenuating the renal oxido-lipidemic stress via regulating NOS level and thereby protects the nephron in hypercholesterolemic rats.
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Affiliation(s)
- Venkatakrishnan Kamesh
- Department of Medical Biochemistry, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras , Taramani Campus, Chennai, Tamil Nadu , India
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Suzuki M, Minami A, Nakanishi A, Kobayashi K, Matsuda S, Ogura Y, Kitagishi Y. Atherosclerosis and tumor suppressor molecules (review). Int J Mol Med 2014; 34:934-40. [PMID: 25069568 DOI: 10.3892/ijmm.2014.1866] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 07/18/2014] [Indexed: 11/06/2022] Open
Abstract
Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage and levels of DNA repair are reduced during dietary lipid lowering. The tumor suppressor molecules play a pivotal role in regulating cell proliferation, DNA repair and cell death, which are important processes in regulating the composition of atherosclerotic plaque. Accordingly, in this review, we discuss the fundamental role of tumor suppressor molecules in regulating atherogenesis. In particular, we discuss how tumor suppressor molecules are activated in the complex environment of atherosclerotic plaque, and regulate growth arrest, cell senescence and the apoptosis of vascular smooth muscle cells, which may protect against the progression of atherosclerosis. In addition, we discuss promising alternatives to the use of medications (such as statin) against atherosclerosis, namely diet, with the use of plant-derived supplements to modulate the expression and/or activity of tumor suppressor molecules. We also summarize the progress of research made on herbs with a focus on the modulatory roles of tumor suppressors, and on the molecular mechanisms underlying the prevention if atherosclerosis, supporting designs for further research in this field.
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Affiliation(s)
- Miho Suzuki
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Akari Minami
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Atsuko Nakanishi
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Keiko Kobayashi
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Yasunori Ogura
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
| | - Yasuko Kitagishi
- Department of Food Science and Nutrition, Nara Women's University, Nishimachi, Nara 630-8506, Japan
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Characterizing the Lipid-Lowering Effects and Antioxidant Mechanisms of Tomato Paste. Biosci Biotechnol Biochem 2014; 72:677-85. [DOI: 10.1271/bbb.70402] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Wu H, Roks AJ. Genomic instability and vascular aging: A focus on nucleotide excision repair. Trends Cardiovasc Med 2014; 24:61-8. [DOI: 10.1016/j.tcm.2013.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Revised: 06/19/2013] [Accepted: 06/20/2013] [Indexed: 11/26/2022]
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Krishnan TR, Velusamy P, Mangaiah S, Srinivasan A, Vadivel SK, Murugaiyan U, Periandavan K. Epigallocatechin-3-gallate restores the Bcl-2 expression in liver of young rats challenged with hypercholesterolemia but not in aged rats: an insight into its disparity of efficacy on advancing age. Food Funct 2014; 5:916-26. [DOI: 10.1039/c3fo60345h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta. Biogerontology 2013; 15:47-64. [PMID: 24243065 PMCID: PMC3905196 DOI: 10.1007/s10522-013-9477-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 11/04/2013] [Indexed: 11/13/2022]
Abstract
Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are potentially harmful to the organism. Most of the senescence hallmarks were common for both RS and SIPS; however, some differences were observed. 32 % of doxorubicin-treated cells were arrested in the G2/M phase of the cell cycle, while 73 % of replicatively senescing cells were arrested in the G1 phase. Moreover, on the basis of alkaline phosphatase activity measurements, we show that a 7-day treatment with doxorubicin (dox), does not cause precocious cell calcification, which is a characteristic feature of RS. We did not observe calcification even though after 7 days of dox-treatment many other markers characteristic for senescent cells were present. It can suggest that dox-induced SIPS does not accelerate the mineralization of vessels. We consider that detailed characterization of the two types of cellular senescence can be useful in in vitro studies of potential anti-aging factors.
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