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Bai R, Yue X, Tian X, Zhao H, Liu Y, Li T, Wu J. Lysophosphatidic acid 2 alleviates deep vein thrombosis via protective endothelial barrier function. Open Med (Wars) 2025; 20:20241137. [PMID: 39927163 PMCID: PMC11806235 DOI: 10.1515/med-2024-1137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/03/2024] [Revised: 12/09/2024] [Accepted: 12/20/2024] [Indexed: 02/11/2025] Open
Abstract
Background The specific role of lysophosphatidic acid 2 (LPA2) in deep vein thrombosis (DVT) remains unclear. Methods An inferior vena cava annulus retraction model of DVT was established in wild-type (WT) and global LPA2 knockout (Lpar2 -/- ) mice. We examined the incidence of DVT, wet weight of thrombus, length of thrombus, assessed endothelial permeability through Evans blue dye assay in vivo, cell viability, and endothelial cell (EC) permeability of mouse inferior vena cava ECs in vitro. Proteomics, histopathology, immunohistochemistry, and western blotting were employed to investigate the role of LPA2 in DVT. Results Lpar2 deficiency increased vascular endothelial permeability and promoted the progression of DVT. Histological examination revealed aggravated inflammation in the thrombus of Lpar2 -/- DVT mice. In vitro, Lpar2 -/- resulted in increased permeability of ECs. Proteomic results indicated that DVT after Lpar2 -/- may be related to tight junction (TJ) protein. LPA2 agonist, 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid, significantly reduced vascular endothelial permeability as well as increased expression of the vascular endothelial TJ protein zonula occludens-1. Conclusion These data provide a novel mechanism of endothelial barrier protection of LPA2 in DVT.
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Affiliation(s)
- Ruifeng Bai
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Xinyang Yue
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing, 100035, China
| | - Xuan Tian
- Department of Vascular Surgery, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Huiru Zhao
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Ying Liu
- Blood Transfusion Department, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin300100, China
| | - Jun Wu
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, 31 Xinjiekou East St., Beijing, 100035, China
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2
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Zhang Q, Yuan Y, Wang B, Gong P, Xiang L. Lysophosphatidic acid regulates implant osseointegration in murine models via YAP. Connect Tissue Res 2025:1-9. [PMID: 39902934 DOI: 10.1080/03008207.2025.2459856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/16/2024] [Accepted: 01/23/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Lysophosphatidic acid (LPA), a simple bioactive lysophospholipid, has been reported to regulate bone homeostasis and bone remodeling. This study aimed to elucidate the function and intrinsic mechanism of LPA in osseointegration in murine models. METHOD We constructed immediate implant models in murine maxillae. Micro-CT, H&E staining, and PCR assays were performed to evaluate the effects of LPA on osseointegration. Furthermore, Prx1-Cre;Yapf/f mice and Sp7-Cre;Yapf/f mice were generated to investigate the role of YAP on LPA-induced osseointegration. RESULT In this study, we identified that LPA might promote bone deposition on the tissue-implant interface and improve osseointegration. In addition, conditional knockout of YAP from MCSs and pre-osteoblasts blunts LPA-induced osteogenesis and osseointegration in mice. CONCLUSION Our data demonstrated that LPA-YAP signaling is particularly important to regulate osseointegration, which expands our understanding of LPA and provide the potential of LPA to be used in osseointegration.
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Affiliation(s)
- Qin Zhang
- Department of Oral Implantology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Ying Yuan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bin Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Xiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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3
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Wang Y, Bai M, Peng Q, Li L, Tian F, Guo Y, Jing C. Angiogenesis, a key point in the association of gut microbiota and its metabolites with disease. Eur J Med Res 2024; 29:614. [PMID: 39710789 DOI: 10.1186/s40001-024-02224-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/09/2024] [Accepted: 12/15/2024] [Indexed: 12/24/2024] Open
Abstract
The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.
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Affiliation(s)
- Yan Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Mingshuai Bai
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Qifan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Ying Guo
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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4
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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5
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Arroyo-Ataz G, Yagüe AC, Breda JC, Mazzilli SA, Jones D. Transcriptional, developmental, and functional parallels of lymphatic and venous smooth muscle. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.18.604042. [PMID: 39091770 PMCID: PMC11291064 DOI: 10.1101/2024.07.18.604042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 08/04/2024]
Abstract
Lymphatic muscle cells (LMCs) are indispensable for lymphatic vessel contraction and their aberrant recruitment or absence is associated with both primary and secondary lymphedema. Despite their critical role in lymphatic vessel function, the transcriptomic and developmental basis that confer the unique contractile properties to LMCs are largely undefined. In this study, we employed single-cell RNA sequencing (scRNAseq), lineage tracing and in vivo imaging to investigate the basis for the hybrid cardiomyocyte and blood vascular smooth muscle cell (SMC) characteristics that have been described for LMCs. Using scRNAseq, the transcriptomes of LMC and venous SMCs from the murine hindlimb exhibited more similarities than differences, although both were markedly distinct from that of arteriole SMCs in the same tissue. Functionally, both lymphatic vessels and blood vessels in the murine hindlimb displayed pulsatile contractility. However, despite expressing genes that overlap with the venous SMC transcriptome, through lineage tracing we show that LMCs do not originate from Myh11+ SMC progenitors. Previous studies have shown that LMCs express cardiac-related genes, whereas in our study we found that arteriole SMCs, but not LMCs, expressed cardiac-related genes. Through lineage tracing, we demonstrate that a subpopulation of LMCs and SMCs originate from WT1+ mesodermal progenitors, which are known to give rise to SMCs. LMCs, however, do not derive from Nkx2.5+ cardiomyocyte progenitors. Overall, our findings suggest that venous SMCs and LMCs and may derive from a related mesodermal progenitor and adopt a similar gene expression program that enable their contractile properties.
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Affiliation(s)
- Guillermo Arroyo-Ataz
- Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, 670 Albany Street, Boston, Massachusetts 02118, USA
| | - Alejandra Carrasco Yagüe
- Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, 670 Albany Street, Boston, Massachusetts 02118, USA
| | - Julia C. Breda
- Department of Medicine, Division of Computational Biomedicine, Boston University Chobanian & Avedisian School of Medicine, 75 E. Newton Street, Boston, Massachusetts 02118, USA
| | - Sarah A. Mazzilli
- Department of Medicine, Division of Computational Biomedicine, Boston University Chobanian & Avedisian School of Medicine, 75 E. Newton Street, Boston, Massachusetts 02118, USA
| | - Dennis Jones
- Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, 670 Albany Street, Boston, Massachusetts 02118, USA
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6
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Koike S, Keino-Masu K, Masu M. Enpp2 haploinsufficiency induces an eye-open-at-birth phenotype in the DBA/2 background. MICROPUBLICATION BIOLOGY 2024; 2024:10.17912/micropub.biology.001212. [PMID: 38725939 PMCID: PMC11079641 DOI: 10.17912/micropub.biology.001212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Subscribe] [Academic Contribution Register] [Received: 02/21/2024] [Revised: 04/12/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024]
Abstract
Autotaxin, encoded by the Enpp2 gene, produces lysophosphatidic acid (LPA), which exerts numerous biological functions via its cognate receptors. Enpp2 null mutant mice die by embryonic day 9.5 owing to aberrant vascular development in the yolk sac, preventing analysis after that period. In this study, we found that Enpp2 heterozygous mice in the DBA/2 genetic background showed an eye-open-at-birth phenotype at high frequency, caused by failure of eyelid closure during the embryonic stage. Notably, wildtype pups from the Enpp2 heterozygous dam showed the phenotype, although at lower frequency, suggesting that maternal LPA affects the embryonic development.
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Affiliation(s)
- Seiichi Koike
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Engineering for Research, University of Toyama, Toyama, Toyama, Japan
| | - Kazuko Keino-Masu
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Masayuki Masu
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
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7
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Karalis T, Poulogiannis G. The Emerging Role of LPA as an Oncometabolite. Cells 2024; 13:629. [PMID: 38607068 PMCID: PMC11011573 DOI: 10.3390/cells13070629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/15/2024] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024] Open
Abstract
Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.
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Affiliation(s)
| | - George Poulogiannis
- Signalling and Cancer Metabolism Laboratory, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;
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8
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Volkmann ER, Denton CP, Kolb M, Wijsenbeek-Lourens MS, Emson C, Hudson K, Amatucci AJ, Distler O, Allanore Y, Khanna D. Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis. Eur Respir Rev 2024; 33:240015. [PMID: 39009409 PMCID: PMC11262619 DOI: 10.1183/16000617.0015-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/25/2024] [Accepted: 04/01/2024] [Indexed: 07/17/2024] Open
Abstract
Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.
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Affiliation(s)
- Elizabeth R Volkmann
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Martin Kolb
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - Claire Emson
- Translational Medicine, Horizon Therapeutics (now Amgen, Inc.), Rockville, MD, USA
| | - Krischan Hudson
- Clinical Development, Horizon Therapeutics (now Amgen, Inc.), Deerfield, IL, USA
| | - Anthony J Amatucci
- Global Medical Affairs, Horizon Therapeutics (now Amgen, Inc), Deerfield, IL, USA
| | - Oliver Distler
- Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Yannick Allanore
- Rheumatology Department, Cochin Hospital APHP, INSERM U1016, Université Paris Cité, Paris, France
| | - Dinesh Khanna
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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9
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Simonetti J, Ficili M, Sgalla G, Richeldi L. Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs 2024; 33:133-143. [PMID: 38299617 DOI: 10.1080/13543784.2024.2305126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
INTRODUCTION Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF. AREAS COVERED The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules. EXPERT OPINION The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.
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Affiliation(s)
- Jacopo Simonetti
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Ficili
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Richeldi
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Unita Operativa Complessa di Pneumologia, Dipartimento di Neuroscienze, Organi di Senso e Torace, Università Cattolica del Sacro Cuore, Rome, Italy
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10
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Aikawa S, Hirota Y. Roles of lipid mediators in early pregnancy events. Reprod Med Biol 2024; 23:e12597. [PMID: 39010880 PMCID: PMC11247399 DOI: 10.1002/rmb2.12597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2024] [Accepted: 06/24/2024] [Indexed: 07/17/2024] Open
Abstract
Background Early pregnancy events, including embryo implantation, are critical for maintaining a healthy pregnancy and facilitating childbirth. Despite numerous signaling pathways implicated in establishing early pregnancy, a comprehensive understanding of implantation remains elusive. Methods This paper provides a comprehensive review of the current research on lipids in the context of early pregnancy, with a particular focus on feto-maternal communications. Main Findings Embryo implantation entails direct interaction between uterine tissues and embryos. Introducing embryos triggers significant changes in uterine epithelial morphology and stromal differentiation, facilitating embryo implantation through communication with uterine tissue. Studies employing genetic models and chemical compounds targeting enzymes and receptors have elucidated the crucial roles of lipid mediators-prostaglandins, lysophosphatidic acid, sphingosine-1-phosphate, and cannabinoids-in early pregnancy events. Conclusion Given the high conservation of lipid synthases and receptors across species, lipid mediators likely play pivotal roles in rodents and humans. Further investigations into lipids hold promise for developing novel diagnostic and therapeutic approaches for infertility in humans.
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Affiliation(s)
- Shizu Aikawa
- Department of Obstetrics and Gynecology Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Yasushi Hirota
- Department of Obstetrics and Gynecology Graduate School of Medicine, The University of Tokyo Tokyo Japan
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11
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Li H, Huang Z, Yang C, Han D, Wang X, Qiu X, Zhang Z, Chen X. Association between plasma lysophosphatidic acid levels and bronchopulmonary dysplasia in extremely preterm infants: A prospective study. Pediatr Pulmonol 2023; 58:3516-3522. [PMID: 37712600 DOI: 10.1002/ppul.26685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/11/2023] [Revised: 08/19/2023] [Accepted: 09/05/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND Lysophosphatidic acid (LPA) is implicated in bronchopulmonary dysplasia (BPD) pathogenesis, but clinical evidence is lacking. This study aimed to investigate LPA levels in preterm infants with and without BPD and explore LPA as a biomarker for predicting BPD occurrence. METHODS Premature infants with a gestational age of <28 weeks or a birth weight of <1000 g were enrolled. Blood samples were collected at postnatal day (PD) 7, 28, and postmenstrual age (PMA) 36 weeks, and plasma LPA levels were measured using a commercial ELISA kit. Receiver operating characteristic curve (ROC) curve analysis determined the PD 28 cutoff for LPA, and multivariable regression analyzed LPA's independent contribution to BPD and exploratory outcomes. RESULT Among the 91 infants enrolled in this study, 35 were classified into the non-BPD group and 56 into the BPD group. Infants with BPD had higher plasma LPA levels at PD 28 (6.467 vs. 4.226 μg/mL, p = 0.034) and PMA 36 weeks (2.330 vs. 1.636 μg/mL, p = 0.001). PD 28 LPA level of 6.132 μg/mL was the cutoff for predicting BPD development. Higher PD 28 LPA levels (≥6.132 μg/mL) independently associated with BPD occurrence (OR 3.307, 95% CI 1.032-10.597, p = 0.044). Higher LPA levels correlated with longer oxygen therapy durations [regression coefficients (β) 0.147, 95% CI 0.643-16.133, p = .034]. CONCLUSIONS Infants with BPD had higher plasma LPA levels at PD 28 and PMA 36 weeks. Higher PD 28 LPA levels independently associated with an increased BPD risk.
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Affiliation(s)
- Huitao Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
- Department of Cardiac Pediatrics, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zilu Huang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Chuanzhong Yang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Dongshan Han
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Xuan Wang
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Xiaomei Qiu
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Zhiwei Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Cardiac Pediatrics, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xueyu Chen
- Department of Neonatology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
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12
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Koike S, Keino-Masu K, Tanimoto Y, Takahashi S, Masu M. The autotaxin-LPA axis promotes membrane trafficking and secretion in yolk sac visceral endoderm cells. Biol Open 2023; 12:bio060081. [PMID: 37795611 PMCID: PMC10629499 DOI: 10.1242/bio.060081] [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] [Academic Contribution Register] [Received: 07/18/2023] [Accepted: 09/28/2023] [Indexed: 10/06/2023] Open
Abstract
Autotaxin, encoded by the Enpp2 gene, is an exoenzyme that produces lysophosphatidic acid, thereby regulating many biologic functions. We previously reported that Enpp2 mRNA was abundantly expressed in yolk sac visceral endoderm (VE) cells and that Enpp2-/- mice were lethal at embryonic day 9.5 owing to angiogenic defects in the yolk sac. Enpp2-/- mice showed lysosome fragmentation in VE cells and embryonic abnormalities including allantois malformation, neural tube defects, no axial turning, and head cavity formation. However, whether the defects in endocytic vesicle formation affect membrane trafficking in VE cells remained to be directly examined. In this study, we found that pinocytosis, transcytosis, and secretion of angiogenic factors such as vascular endothelial growth factor and transforming growth factor β1 were impaired in Enpp2-/- VE cells. Moreover, pharmacologic inhibition of membrane trafficking phenocopied the defects of Enpp2-/- mice. These findings demonstrate that Enpp2 promotes endocytosis and secretion of angiogenic factors in VE cells, thereby regulating angiogenesis/vasculogenesis and embryonic development.
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Affiliation(s)
- Seiichi Koike
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
- Laboratory of Organelle Synthetic Biology, Graduate School of Science and Engineering for Research, University of Toyama, 3190 Gofuku, Toyama-shi, Toyama 930-855, Japan
| | - Kazuko Keino-Masu
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoko Tanimoto
- Laboratory Animal Resource Center and Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center and Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Masayuki Masu
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
- Department of Molecular Neurobiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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13
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Bai R, Pei J, Pei S, Cong X, Chun J, Wang F, Chen X. LPA 2 Alleviates Septic Acute Lung Injury via Protective Endothelial Barrier Function Through Activation of PLC-PKC-FAK. J Inflamm Res 2023; 16:5095-5109. [PMID: 38026263 PMCID: PMC10640838 DOI: 10.2147/jir.s419578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/27/2023] [Accepted: 09/27/2023] [Indexed: 12/01/2023] Open
Abstract
Background Increased endothelial permeability of pulmonary vessels is a primary pathological characteristic of septic acute lung injury (ALI). Previously, elevated lysophosphatidic acid (LPA) levels and LPA2 (an LPA receptor) expression have been found in the peripheral blood and lungs of septic mice, respectively. However, the specific role of LPA2 in septic ALI remains unclear. Methods A lipopolysaccharide (LPS)-induced model of sepsis was established in wild-type (WT) and global LPA2 knockout (Lpar2-/-) mice. We examined mortality, lung injury, assessed endothelial permeability through Evans blue dye (EBD) assay in vivo, and transendothelial electrical resistance (TEER) of mouse lung microvascular endothelial cells (MLMECs) in vitro. Enzyme-linked immunosorbent assay (ELISA), histopathological, immunofluorescence, immunohistochemistry, and Western blot were employed to investigate the role of LPA2 in septic ALI. Results Lpar2 deficiency increased vascular endothelial permeability, impaired lung injury, and increased mortality. Histological examination revealed aggravated inflammation, edema, hemorrhage and alveolar septal thickening in the lungs of septic Lpar2-/- mice. In vitro, loss of Lpar2 resulted in increased permeability of MLMECs. Pharmacological activation of LPA2 by the agonist DBIBB led to significantly reduced inflammation, edema and hemorrhage, as well as increased expression of the vascular endothelial tight junction (TJ) protein zonula occludens-1 (ZO-1) and claudin-5, as well as the adheren junction (AJ) protein VE-cadherin. Moreover, DBIBB treatment was found to alleviate mortality by protecting against vascular endothelial permeability. Mechanistically, we demonstrated that vascular endothelial permeability was alleviated through LPA-LPA2 signaling via the PLC-PKC-FAK pathway. Conclusion These data provide a novel mechanism of endothelial barrier protection via PLC-PKC-FAK pathway and suggest that LPA2 may contribute to the therapeutic effects of septic ALI.
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Affiliation(s)
- Ruifeng Bai
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Jianqiu Pei
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Shengqiang Pei
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Xiangfeng Cong
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Jerold Chun
- Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Fang Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Diagnostic Laboratory Service, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Clinical Laboratory, Fuwai Yunnan Cardiovascular Hospital, Kunming, People’s Republic of China
| | - Xi Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Diagnostic Laboratory Service, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
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14
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Cerutis DR, Weston MD, Miyamoto T. Entering, Linked with the Sphinx: Lysophosphatidic Acids Everywhere, All at Once, in the Oral System and Cancer. Int J Mol Sci 2023; 24:10278. [PMID: 37373424 PMCID: PMC10299546 DOI: 10.3390/ijms241210278] [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] [Academic Contribution Register] [Received: 05/04/2023] [Revised: 06/08/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Oral health is crucial to overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Over the past decade, PDD has been recognized as a significant contributor to systemic inflammation. Here, we relate our seminal work defining the role of lysophosphatidic acid (LPA) and its receptors (LPARs) in the oral system with findings and parallels relevant to cancer. We discuss the largely unexplored fine-tuning potential of LPA species for biological control of complex immune responses and suggest approaches for the areas where we believe more research should be undertaken to advance our understanding of signaling at the level of the cellular microenvironment in biological processes where LPA is a key player so we can better treat diseases such as PDD, cancer, and emerging diseases.
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Affiliation(s)
- D. Roselyn Cerutis
- Department of Oral Biology, Creighton University School of Dentistry, Omaha, NE 68178, USA;
| | - Michael D. Weston
- Department of Oral Biology, Creighton University School of Dentistry, Omaha, NE 68178, USA;
| | - Takanari Miyamoto
- Department of Periodontics, Creighton University School of Dentistry, Omaha, NE 68178, USA;
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15
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Magkrioti C, Kaffe E, Aidinis V. The Role of Autotaxin and LPA Signaling in Embryonic Development, Pathophysiology and Cancer. Int J Mol Sci 2023; 24:ijms24098325. [PMID: 37176032 PMCID: PMC10179533 DOI: 10.3390/ijms24098325] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/20/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Autotaxin (ATX) or Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a secreted enzyme with lysophospholipase D activity, with its primary function being the extracellular hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid [...].
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Affiliation(s)
- Christiana Magkrioti
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
| | - Eleanna Kaffe
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
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16
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Yanagida K, Shimizu T. Lysophosphatidic acid, a simple phospholipid with myriad functions. Pharmacol Ther 2023; 246:108421. [PMID: 37080433 DOI: 10.1016/j.pharmthera.2023.108421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/08/2023] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical structure, LPA plays an important role as an essential bioactive signaling molecule via its specific six G protein-coupled receptors, LPA1-6. Recent studies, especially those using genetic tools, have revealed diverse physiological and pathological roles of LPA and LPA receptors in almost every organ system. Furthermore, many studies are illuminating detailed mechanisms to orchestrate multiple LPA receptor signaling pathways and to facilitate their coordinated function. Importantly, these extensive "bench" works are now translated into the "bedside" as exemplified by approaches targeting LPA1 signaling to combat fibrotic diseases. In this review, we discuss the physiological and pathological roles of LPA signaling and their implications for clinical application by focusing on findings revealed by in vivo studies utilizing genetic tools targeting LPA receptors.
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Affiliation(s)
- Keisuke Yanagida
- Department of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan.
| | - Takao Shimizu
- Department of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan; Institute of Microbial Chemistry, Tokyo, Japan
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17
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Dacheux MA, Norman DD, Tigyi GJ, Lee SC. Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer. Pharmacol Ther 2023; 245:108414. [PMID: 37061203 DOI: 10.1016/j.pharmthera.2023.108414] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that regulates a variety of cellular functions such as cell proliferation, migration, survival, calcium mobilization, cytoskeletal rearrangements, and neurite retraction. The biological actions of LPA are mediated by at least six G protein-coupled receptors known as LPAR1-6. Given that LPAR1-3 were among the first LPARs identified, the majority of research efforts have focused on understanding their biology. This review provides an in-depth discussion of LPAR5, which has recently emerged as a key player in regulating normal intestinal homeostasis and modulating pathological conditions such as pain, itch, inflammatory diseases, and cancer. We also present a chronological overview of the efforts made to develop compounds that target LPAR5 for use as tool compounds to probe or validate LPAR5 biology and therapeutic agents for the treatment of inflammatory diseases and cancer.
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Affiliation(s)
- Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Gábor J Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America.
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18
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Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway. Cells 2023; 12:cells12040548. [PMID: 36831215 PMCID: PMC9954511 DOI: 10.3390/cells12040548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2023] [Revised: 02/03/2023] [Accepted: 02/04/2023] [Indexed: 02/10/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient's survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid "lysophosphatidic acid (LPA)" and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF.
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19
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Subedi U, Manikandan S, Bhattarai S, Sharma P, Sharma S, Sun H, Miriyala S, Panchatcharam M. The Autotaxin-LPA Axis Emerges as a Novel Regulator of Smooth Muscle Cell Phenotypic Modulation during Intimal Hyperplasia. Int J Mol Sci 2023; 24:2913. [PMID: 36769255 PMCID: PMC9917461 DOI: 10.3390/ijms24032913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Neointimal hyperplasia is characterized by a loss of the contractile phenotype of vascular smooth muscle cells (VSMCs). Our group has recently shown that VSMC proliferation and migration are mediated by lysophosphatidic acid (LPA) during restenosis, but the role of autotaxin (ATX; lysophospholipase D), which produces LPA, remains unclear. Endothelial denudation of the mouse carotid artery was performed to induce neointimal hyperplasia, and the extent of damage caused by the ATX-LPA axis was assessed in VSMCs. We observed the upregulation of ATX activity (p < 0.0002) in the injured carotid artery using an AR2 probe fluorescence assay. Further, the tissue carotid LPA levels were elevated 2.7-fold in carotid vessels, augmenting neointimal hyperplasia. We used an electrical cell-substrate impedance sensor (ECIS) to measure VSMC proliferation and migration. Treatment with an ATX inhibitor (PF8380) or LPA receptor inhibitor (Ki16425) attenuated VSMC proliferation (extracellular signal-regulated kinases) activity and migration in response to recombinant ATX. Indeed, PF8380 treatment rescued the aggravated post-wire injury neointima formation of carotid arteries. The upregulation of ATX following vessel injury leads to LPA production in VSMCs, favoring restenosis. Our observations suggest that inhibition of the ATX-LPA axis could be therapeutically targeted in restenosis to minimize VSMC phenotypic modulation and inflammation after vascular injury.
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Affiliation(s)
| | | | | | | | | | | | - Sumitra Miriyala
- Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences-Shreveport, Shreveport, LA 71130, USA
| | - Manikandan Panchatcharam
- Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences-Shreveport, Shreveport, LA 71130, USA
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20
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Wiskott K, Gilardi F, Hainard A, Sanchez JC, Thomas A, Sajic T, Fracasso T. Blood proteome of acute intracranial hemorrhage in infant victims of abusive head trauma. Proteomics 2023; 23:e2200078. [PMID: 36576318 DOI: 10.1002/pmic.202200078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/18/2022] [Revised: 12/02/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022]
Abstract
Abusive head trauma (AHT) is a leading cause of mortality and morbidity in infants. While the reported incidence is close to 40 cases per 100'000 births/year, misdiagnoses are commonly observed in cases with atypical, subacute, or chronic presentation. Currently, standard clinical evaluation of inflicted intracranial hemorrhagic injury (ICH) in infants urgently requires a screening test able to identify infants who need additional investigations. Blood biomarkers characteristic of AHT may assist in detecting these infants, improving prognosis through early medical care. To date, the application of innovative omics technologies in retrospective studies of AHT in infants is rare, due also to the blood serum and cerebrospinal fluid of AHT cases being scarce and not systematically accessible. Here, we explored the circulating blood proteomes of infants with severe AHT and their atraumatic controls. We discovered 165 circulating serum proteins that display differential changes in AHT cases compared with atraumatic controls. The peripheral blood proteomes of pediatric AHT commonly reflect: (i) potentially secreted proteome from injured brain, and (ii) proteome dysregulated in the system's circulation by successive biological events following acute ICH. This study opens up a novel opportunity for research efforts in clinical screening of AHT cases.
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Affiliation(s)
- Kim Wiskott
- Forensic medicine unit, University Center of Legal Medicine, Geneva 4, Switzerland
| | - Federica Gilardi
- Faculty Unit of Toxicology, University Center of Legal Medicine, Lausanne University Hospital, Lausanne 25, Switzerland.,Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital and Geneva University Hospital, Geneva, Switzerland
| | - Alexandre Hainard
- Proteomics Core Facility, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jean-Charles Sanchez
- Translational Biomarker Group, Department of Internal Medicine, University of Geneva, Geneva, Switzerland
| | - Aurelien Thomas
- Faculty Unit of Toxicology, University Center of Legal Medicine, Lausanne University Hospital, Lausanne 25, Switzerland.,Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital and Geneva University Hospital, Geneva, Switzerland
| | - Tatjana Sajic
- Faculty Unit of Toxicology, University Center of Legal Medicine, Lausanne University Hospital, Lausanne 25, Switzerland.,Unit of Forensic Toxicology and Chemistry, CURML, Lausanne University Hospital and Geneva University Hospital, Geneva, Switzerland
| | - Tony Fracasso
- Forensic medicine unit, University Center of Legal Medicine, Geneva 4, Switzerland
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21
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Méaux MN, Regnier M, Portefaix A, Borel O, Alioli C, Peyruchaud O, Legrand M, Bacchetta J. Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort. Front Pediatr 2023; 11:1094705. [PMID: 36861069 PMCID: PMC9969100 DOI: 10.3389/fped.2023.1094705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/10/2022] [Accepted: 01/16/2023] [Indexed: 02/17/2023] Open
Abstract
Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.
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Affiliation(s)
- Marie-Noëlle Méaux
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Maitena Regnier
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Aurélie Portefaix
- Centre d'Investigation Clinique, CIC 1407, Hospices Civils de Lyon, Bron, France
| | | | | | | | - Mélanie Legrand
- INSERM, UMR 1033, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Service de Rhumatologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Justine Bacchetta
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
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22
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [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] [Academic Contribution Register] [Indexed: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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23
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Contreras O, Harvey RP. Single-cell transcriptome dynamics of the autotaxin-lysophosphatidic acid axis during muscle regeneration reveal proliferative effects in mesenchymal fibro-adipogenic progenitors. Front Cell Dev Biol 2023; 11:1017660. [PMID: 36910157 PMCID: PMC9996314 DOI: 10.3389/fcell.2023.1017660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/12/2022] [Accepted: 02/08/2023] [Indexed: 02/25/2023] Open
Abstract
Lysophosphatidic acid is a growth factor-like bioactive phospholipid recognising LPA receptors and mediating signalling pathways that regulate embryonic development, wound healing, carcinogenesis, and fibrosis, via effects on cell migration, proliferation and differentiation. Extracellular LPA is generated from lysophospholipids by the secreted hydrolase-ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; also, AUTOTAXIN/ATX) and metabolised by different membrane-bound phospholipid phosphatases (PLPPs). Here, we use public bulk and single-cell RNA sequencing datasets to explore the expression of Lpar 1-6, Enpp2, and Plpp genes under skeletal muscle homeostasis and regeneration conditions. We show that the skeletal muscle system dynamically expresses the Enpp2-Lpar-Plpp gene axis, with Lpar1 being the highest expressed member among LPARs. Lpar1 was expressed by mesenchymal fibro-adipogenic progenitors and tenocytes, whereas FAPs mainly expressed Enpp2. Clustering of FAPs identified populations representing distinct cell states with robust Lpar1 and Enpp2 transcriptome signatures in homeostatic cells expressing higher levels of markers Dpp4 and Hsd11b1. However, tissue injury induced transient repression of Lpar genes and Enpp2. The role of LPA in modulating the fate and differentiation of tissue-resident FAPs has not yet been explored. Ex vivo, LPAR1/3 and ENPP2 inhibition significantly decreased the cell-cycle activity of FAPs and impaired fibro-adipogenic differentiation, implicating LPA signalling in the modulation of the proliferative and differentiative fate of FAPs. Together, our results demonstrate the importance of the ENPP2-LPAR-PLPP axis in different muscle cell types and FAP lineage populations in homeostasis and injury, paving the way for further research on the role of this signalling pathway in skeletal muscle homeostasis and regeneration, and that of other organs and tissues, in vivo.
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Affiliation(s)
- Osvaldo Contreras
- Developmental and Regenerative Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, UNSW Sydney, Sydney, NSW, Australia
| | - Richard P Harvey
- Developmental and Regenerative Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, UNSW Sydney, Sydney, NSW, Australia.,School of Biotechnology and Biomolecular Science, University of New South Wales, UNSW Sydney, Sydney, NSW, Australia
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24
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Spencer SA, Suárez-Pozos E, Verdugo JS, Wang H, Afshari FS, Li G, Manam S, Yasuda D, Ortega A, Lister JA, Ishii S, Zhang Y, Fuss B. Lysophosphatidic acid signaling via LPA 6 : A negative modulator of developmental oligodendrocyte maturation. J Neurochem 2022; 163:478-499. [PMID: 36153691 PMCID: PMC9772207 DOI: 10.1111/jnc.15696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/22/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 01/14/2023]
Abstract
The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.
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Affiliation(s)
- Samantha A Spencer
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Edna Suárez-Pozos
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Jazmín Soto Verdugo
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - Huiqun Wang
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Fatemah S Afshari
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Guo Li
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Susmita Manam
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Daisuke Yasuda
- Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México
| | - James A Lister
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Satoshi Ishii
- Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan
| | - Yan Zhang
- Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia, USA
| | - Babette Fuss
- Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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25
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Süzen Çaypınar S, Oğlak SC, Behram M, Gedik Özköse Z, Sezer S, Karakaş S. Serum autotaxin levels correlate with the severity of pruritus in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2022; 48:3093-3102. [PMID: 36164271 DOI: 10.1111/jog.15444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/16/2022] [Revised: 08/25/2022] [Accepted: 09/14/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE This study aimed to examine autotaxin (ATX) concentrations in the serum of pregnant women complicated with intrahepatic cholestasis of pregnancy (ICP) and compare them with individuals with uncomplicated healthy pregnancies. METHODS This prospective case-control study took place with 83 pregnant women. The study group included 43 pregnant women presenting with a singleton pregnancy diagnosed with ICP in their third trimester of pregnancy. The diagnostic power of the ATX variable was examined by receiver operating characteristic analysis, and the cut-off value calculated according to the Youden index was summarized with the related sensitivity and specificity points. RESULTS The mean serum concentration of maternal ATX was significantly higher in the ICP cases (8.91 ± 2.69 pg/mL) compared to the pregnant women in the control group (3.59 ± 1.39 ng/mL, p < 0.001). According to the Youden index, a 5.80 ng/mL cut-off value of serum ATX concentrations can be used to diagnose ICP with 97.7% sensitivity and 97.5% specificity. A significant highly positive correlation was found between maternal serum ATX levels and maternal serum total bile acid levels (r = 0.633 and p < 0.001) and itch intensity, which was objectified by the visual analog scale score (r = 0.951 and p < 0.001). CONCLUSION Maternal serum ATX levels were significantly increased in ICP patients as compared with healthy pregnant women. Also, serum ATX activity was highly correlated with the itch intensity. We consider that ATX might represent a robust, accurate, and reliable circulating biomarker to diagnose ICP.
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Affiliation(s)
- Sema Süzen Çaypınar
- Department of Perinatology, Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey
| | - Süleyman Cemil Oğlak
- Department of Obstetrics and Gynecology, Health Sciences University, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey
| | - Mustafa Behram
- Department of Perinatology, Health Sciences University, Antalya Training and Research Hospital, Istanbul, Turkey
| | - Zeynep Gedik Özköse
- Department of Perinatology, Health Sciences University, Kanuni Sultan Süleyman Training and Research Hospital, Istanbul, Turkey
| | - Salim Sezer
- Department of Perinatology, Esenyurt University Hospital, Istanbul, Turkey
| | - Sema Karakaş
- Department of Gynecologic Oncology, Health Sciences University, Bakırköy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey
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26
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Kalamatianos T, Drosos E, Magkrioti C, Nikitopoulou I, Koutsarnakis C, Kotanidou A, Paraskevas GP, Aidinis V, Stranjalis G. Autotaxin Activity in Chronic Subdural Hematoma: A Prospective Clinical Study. Diagnostics (Basel) 2022; 12:diagnostics12081865. [PMID: 36010216 PMCID: PMC9406550 DOI: 10.3390/diagnostics12081865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/06/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022] Open
Abstract
Autotaxin (ATX) is the ectoenzyme producing the bulk of lysophosphatidic acid (LPA) in circulation. ATX and LPA-mediated signaling (the ATX-LPA axis) play critical roles in the vascular and nervous system development. In adults, this axis contributes to diverse processes, including coagulation, inflammation, fibroproliferation and angiogenesis under physiological and/or pathophysiological conditions. Given evidence implicating several of these processes in chronic subdural hematoma (CSDH) pathogenesis and development, we assessed ATX activity in CSDH patients. Twenty-eight patients were recruited. Blood and hematoma fluid were collected. Enzymatic assays were used to establish serum and hematoma ATX activity. Enzyme-linked immunosorbent assays were used to establish hematoma beta trace (BT) levels, a cerebrospinal fluid (CSF) marker, in a hematoma. ATX activity was nearly three folds higher in hematoma compared to serum (P < 0.001). There was no significant correlation between BT levels and ATX activity in a hematoma. The present results show, for the first time, that ATX is catalytically active in the hematoma fluid of CSDH patients. Moreover, our findings of significantly elevated ATX activity in hematoma compared to serum, implicate the ATX-LPA axis in CSDH pathophysiology. The CSF origin of ATX could not be inferred with the present results. Additional research is warranted to establish the significance of the ATX-LPA axis in CSDH and its potential as a biomarker and/or therapeutic target.
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Affiliation(s)
- Theodosis Kalamatianos
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
- Hellenic Centre for Neurosurgery Research, “Professor Petros S. Kokkalis”, 106 75 Athens, Greece
- Correspondence:
| | - Evangelos Drosos
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
| | - Christiana Magkrioti
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 166 72 Athens, Greece; (C.M.); (V.A.)
| | - Ioanna Nikitopoulou
- GP Livanos and M Simou Laboratories, 1st Department of Critical Care & Pulmonary Services, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece;
| | - Christos Koutsarnakis
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
| | - Anastasia Kotanidou
- 1st Department of Critical Care & Pulmonary Services, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece;
| | - George P. Paraskevas
- 2nd Department of Neurology, School of Medicine, “Attikon” General Hospital, National and Kapodistrian University of Athens, 124 62 Athens, Greece;
| | - Vassilis Aidinis
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 166 72 Athens, Greece; (C.M.); (V.A.)
| | - George Stranjalis
- Department of Neurosurgery, Faculty of Health Sciences, School of Medicine, Evaggelismos General Hospital, National and Kapodistrian University of Athens, 106 76 Athens, Greece; (E.D.); (C.K.); (G.S.)
- Hellenic Centre for Neurosurgery Research, “Professor Petros S. Kokkalis”, 106 75 Athens, Greece
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27
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Takagi Y, Nishikado S, Omi J, Aoki J. The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field. Biol Pharm Bull 2022; 45:1008-1021. [DOI: 10.1248/bpb.b22-00304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yugo Takagi
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
| | - Shun Nishikado
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
| | - Jumpei Omi
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
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28
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Autotaxin Has a Negative Role in Systemic Inflammation. Int J Mol Sci 2022; 23:ijms23147920. [PMID: 35887265 PMCID: PMC9322786 DOI: 10.3390/ijms23147920] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/26/2022] [Revised: 07/08/2022] [Accepted: 07/14/2022] [Indexed: 02/05/2023] Open
Abstract
The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.
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29
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Yang X, Zhao G, Bo Y, Yang D, Dong Z, Wu G, Xu N, An M, Zhao L. Mechanisms exploration of Terrestrosin D on pulmonary fibrosis based on plasma metabolomics and network pharmacology. Biomed Chromatogr 2022; 36:e5441. [PMID: 35789496 DOI: 10.1002/bmc.5441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/22/2022] [Revised: 06/14/2022] [Accepted: 06/30/2022] [Indexed: 11/08/2022]
Abstract
Terrestrosin D (TED) is the active ingredient of Tribulus terrestris L., which is used in traditional Chinese medicine (TCM) formulations and has a wide range of pharmacological activities. A previous study showed that TED alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice. However, the mechanisms underlying the therapeutic effect of TED are still unclear and need further investigation. In this study, we evaluated the effect of TED in a mice of BLM-induced PF in terms of histopathological and biochemical indices. UHPLC-MS-based plasma metabolomics combined with network pharmacology was used to explore the pathological basis of PF and the mechanism of action of TED. Histological and biochemical analyses showed that TED mitigated inflammatory injury in the lungs, especially at the dosage of 20 mg/kg. Furthermore, BLM changed the plasma metabolite profile in the mice, which was reversed by TED via regulation of amino acid and lipid metabolism. Subsequently, a biomarkers-targets-disease network was constructed, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 were identified as the putative therapeutic targets of TED. Both factors were quantitatively analyzed by enzyme-linked immunosorbent assay (ELISA). Taken together, the combination of UHPLC-MS-based metabolomics and network pharmacology can unveil the mechanisms of diseases and drug action.
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Affiliation(s)
- Xuemiao Yang
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Guojun Zhao
- Department of Pharmacy, Baotou Fourth Hospital, Baotou, Inner Mongolia, P. R. China
| | - Yukun Bo
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Dan Yang
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Zhiqiang Dong
- Clinical Pharmacy, First Affiliated Hospital, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Guodong Wu
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Nanbing Xu
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Ming An
- School of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia, P. R. China
| | - Longshan Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
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30
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Rafiyan M, Abadi MHJN, Zadeh SST, Hamblin MR, Mousavi M, Mirzaei H. Lysophosphatidic Acid Signaling and microRNAs: New Roles in Various Cancers. Front Oncol 2022; 12:917471. [PMID: 35814375 PMCID: PMC9259992 DOI: 10.3389/fonc.2022.917471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/11/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
A wide range of microRNAs (miRNAs) are coded for in the human genome and contribute to the regulation of gene expression. MiRNAs are able to degrade mRNAs and/or prevent the RNA transcript from being translated through complementary binding of the miRNA seed region (nucleotide 2-8) to the 3'-untranslated regions of many mRNAs. Although miRNAs are involved in almost all processes of normal human cells, they are also involved in the abnormal functions of cancer cells. MiRNAs can play dual regulatory roles in cancer, acting either as tumor suppressors or as tumor promoters, depending on the target, tumor type, and stage. In the current review, we discuss the present status of miRNA modulation in the setting of lysophosphatidic acid (LPA) signaling. LPA is produced from lysophosphatidylcholine by the enzyme autotaxin and signals via a range of G protein-coupled receptors to affect cellular processes, which ultimately causes changes in cell morphology, survival, proliferation, differentiation, migration, and adhesion. Several studies have identified miRNAs that are over-expressed in response to stimulation by LPA, but their functional roles have not yet been fully clarified. Since RNA-based treatments hold tremendous promise in the area of personalized medicne, many efforts have been made to bring miRNAs into clinical trials, and this field is evolving at an increasing pace.
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Affiliation(s)
- Mahdi Rafiyan
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Mahboubeh Mousavi
- Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Hamed Mirzaei
- Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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31
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Yonezu Y, Tanabe S, Misawa H, Muramatsu R. Lysophosphatidic acid stimulates pericyte migration via LPA receptor 1. Biochem Biophys Res Commun 2022; 618:61-66. [PMID: 35716596 DOI: 10.1016/j.bbrc.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/19/2022] [Accepted: 06/06/2022] [Indexed: 11/02/2022]
Abstract
Lysophosphatidic acid (LPA) is a bioactive compound known to regulate various vascular functions. However, despite the fact that many vascular functions are regulated by peri-vascular cells such as pericytes, the effect of LPA on brain pericytes has not been fully evaluated. Thus, we designed this study to evaluate the effects of LPA on brain pericytes. These experiments revealed that while LPA receptors (LPARs) are expressed in cultured pericytes from mouse brains, LPA treatment does not influence the proliferation of these cells but does have a profound impact on their migration, which is regulated via the expression of LPAR1. LPAR1 expression was also detected in human pericyte culture and LPA treatment of these cells also induced migration. Taken together these findings imply that LPA-LPAR1 signaling is one of the key mechanisms modulating pericyte migration, which may help to control vascular function during development and repair processes.
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Affiliation(s)
- Yoshino Yonezu
- Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, 105-8512, Japan
| | - Shogo Tanabe
- Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan
| | - Hidemi Misawa
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, 105-8512, Japan
| | - Rieko Muramatsu
- Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, 187-8502, Japan.
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32
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Deng L, Li Z, Tang C, Han Y, Zhang L, Liao Q. Quantitative analysis of the serum proteome during early pregnancy in mares. Anim Sci J 2022; 93:e13727. [PMID: 35476278 DOI: 10.1111/asj.13727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/11/2021] [Revised: 02/02/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
Abstract
Equine pregnancy is currently diagnosed by rectal palpation, ultrasonographic examination, or by measuring changes in hormones in the blood. In the present study, we identified proteins that are differentially expressed in the sera of early pregnant and non-pregnant mares in order to develop a novel method for diagnosing equine pregnancy. Serum samples were obtained from 18 adult mares, pregnancy at day 32 after ovulation (n = 9) and in diestrus (n = 9). Proteomic analysis of the samples was conducted using liquid chromatography-electrospray ionization-tandem mass spectrometry. We identified 467 proteins from a total of 3514 peptides. Thirty-two proteins (15 upregulated and 17 downregulated) were significantly differentially expressed between the two groups. The Gene Ontology enrichment analysis revealed that they are related to extracellular matrix assembly, blood coagulation, and hemostasis, and the prominent molecular functions were integrin binding, cell adhesion molecule binding, and glycine C-acetyltransferase activity. The pathway analysis of Kyoto Encyclopaedia of Genes and Genomes showed that the top three pathways identified were glycine, serine, and threonine metabolism; cysteine and methionine metabolism; and ether lipid metabolism. The selected five serum proteins were newly potential candidates for pregnancy diagnosis in mares.
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Affiliation(s)
- Liang Deng
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Zheng Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Chi Tang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China.,Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, College of Life Sciences, Tarim University, Alar, China
| | - Yuwei Han
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Linxi Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Qingchao Liao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
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33
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The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion. Int J Mol Sci 2022; 23:ijms23084138. [PMID: 35456953 PMCID: PMC9024554 DOI: 10.3390/ijms23084138] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/11/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 11/29/2022] Open
Abstract
Endothelial permeability is a major complication that must be addressed during stroke treatment. Study of the mechanisms underlying blood−brain barrier (BBB) disruption and management of the hypoxic stress-induced permeability of the endothelium following reperfusion are both urgently needed for stroke management. Lysophosphatidic acid (LPA), a bioactive lipid essential for basic cellular functions, causes unfavorable outcomes during stroke progression. LPA-producing enzyme autotaxin (ATX) is regulated in ischemic stroke. We used an electrical cell-substrate impedance sensor (ECIS) to measure endothelial permeability. Mitochondrial bioenergetics were obtained using a Seahorse analyzer. AR-2 probe fluorescence assay was used to measure ATX activity. LPA increased endothelial permeability and reduced junctional protein expression in mouse brain microvascular endothelial cells (MBMEC). LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins. LPA significantly diminished mitochondrial function in MBMEC. ATX was upregulated (p < 0.05) in brain microvascular endothelial cells under hypoxic reperfusion. ATX activity and permeability were attenuated with the use of an ATX inhibitor in a mouse stroke model. The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX−LPA−LPAR axis could be therapeutically targeted in stroke to achieve better outcomes.
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34
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Bano S, Al-Rashida M, Alharthy RD, Khan IA, Iqbal J. Nucleotide pyrophosphatase/phosphodiesterases (NPPs) including NPP1 and NPP2/ ATX as important drug targets: A patent review (2015-2020). Expert Opin Ther Pat 2022; 32:743-751. [PMID: 35333684 DOI: 10.1080/13543776.2022.2058874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Nucleoside triphosphate diphosphohydrolases (NTPDases), alkaline phosphatases (APs), and ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) are nucleotidases found on the cell surface. It is a promising therapeutic target for a range of disorders, including fibrosis, tumour metastasis, pruritus, inflammation, multiple sclerosis, and autoimmune diseases. As a result, therapeutic intervention including selective inhibitors of NPPs is required. AREA COVERED Many chemical substances, including pyrazole, pyridine and bicyclic compounds have demonstrated promising inhibitory potential for ecto-nucleotide pyrophosphatase/phosphodiesterases. The chemistry and clinical applications of NPPs inhibitors patented between 2015 and 2020 are discussed in this review. EXPERT OPINION : In recent years, there has been a lot of effort put into finding effective and selective inhibitors of NPPs. Despite the fact that a variety of synthetic inhibitors have been created, only a few investigations on their in vivo activity have been published. In addition to IOA-289 which has passed Phase Ia clinical trials; potent ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP with a variety of structural characteristics and favourable therapeutic activities.
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Affiliation(s)
- Sehrish Bano
- Center for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
| | - Mariya Al-Rashida
- Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan
| | - Rima D Alharthy
- Department of Chemistry, Science and Arts College, Rabigh Campus, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Imtiaz Ali Khan
- Department of Entomology, Agricultural University, Peshawar 25130, Khyber Pakhtunkhwa, Pakistan
| | - Jamshed Iqbal
- Center for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan
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35
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Alioli C, Demesmay L, Peyruchaud O, Machuca-Gayet I. Autotaxin/Lysophosphatidic Acid Axis: From Bone Biology to Bone Disorders. Int J Mol Sci 2022; 23:ijms23073427. [PMID: 35408784 PMCID: PMC8998661 DOI: 10.3390/ijms23073427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/04/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 02/01/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass.
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Guo P, Tai Y, Wang M, Sun H, Zhang L, Wei W, Xiang YK, Wang Q. Gα 12 and Gα 13: Versatility in Physiology and Pathology. Front Cell Dev Biol 2022; 10:809425. [PMID: 35237598 PMCID: PMC8883321 DOI: 10.3389/fcell.2022.809425] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/05/2021] [Accepted: 01/17/2022] [Indexed: 01/14/2023] Open
Abstract
G protein-coupled receptors (GPCRs), as the largest family of receptors in the human body, are involved in the pathological mechanisms of many diseases. Heterotrimeric G proteins represent the main molecular switch and receive cell surface signals from activated GPCRs. Growing evidence suggests that Gα12 subfamily (Gα12/13)-mediated signaling plays a crucial role in cellular function and various pathological processes. The current research on the physiological and pathological function of Gα12/13 is constantly expanding, Changes in the expression levels of Gα12/13 have been found in a wide range of human diseases. However, the mechanistic research on Gα12/13 is scattered. This review briefly describes the structural sequences of the Gα12/13 isoforms and introduces the coupling of GPCRs and non-GPCRs to Gα12/13. The effects of Gα12/13 on RhoA and other signaling pathways and their roles in cell proliferation, migration, and immune cell function, are discussed. Finally, we focus on the pathological impacts of Gα12/13 in cancer, inflammation, metabolic diseases, fibrotic diseases, and circulatory disorders are brought to focus.
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Affiliation(s)
- Paipai Guo
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yu Tai
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Manman Wang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Hanfei Sun
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yang K Xiang
- Department of Pharmacology, University of California, Davis, Davis, CA, United States.,VA Northern California Health Care System, Mather, CA, United States
| | - Qingtong Wang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
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Hasse S, Julien AS, Duchez AC, Zhao C, Boilard E, Fortin PR, Bourgoin SG. Red blood cell-derived phosphatidylserine positive extracellular vesicles are associated with past thrombotic events in patients with systemic erythematous lupus. Lupus Sci Med 2022; 9:9/1/e000605. [PMID: 35260475 PMCID: PMC8905995 DOI: 10.1136/lupus-2021-000605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/21/2021] [Accepted: 02/18/2022] [Indexed: 12/14/2022]
Abstract
Background Extracellular vesicles (EVs) released by blood cells have proinflammation and procoagulant action. Patients with systemic lupus erythematosus (SLE) present high vascular inflammation and are prone to develop cardiovascular diseases. Therefore, we postulated that the EV populations found in blood, including platelet EVs (PEVs) and red blood cell EVs (REVs), are associated with SLE disease activity and SLE-associated cardiovascular accidents. Method We assessed autotaxin (ATX) plasma levels by ELISA, the platelet activation markers PAC1 and CD62P, ATX bound to platelets and the amounts of plasma PEVs and REVs by flow cytometry in a cohort of 102 patients with SLE, including 29 incident cases of SLE and 30 controls. Correlation analyses explored the associations with the clinical parameters. Result Platelet activation markers were increased in patients with SLE compared with healthy control, with the marker CD62P associated with the SLE disease activity index (SLEDAI). The incident cases show additional associations between platelet markers (CD62P/ATX and PAC1/CD62P) and the SLEDAI. Compared with controls, patients with SLE presented higher levels of PEVs, phosphatidylserine positive (PS+) PEVs, REVs and PS+ REVs, but there is no association with disease activity. When stratified according to the plasma level of PS+ REVs, the group of patients with SLE with a high level of PS+ REVs presented a higher number of past thrombosis events and higher ATX levels. Conclusion Incident and prevalent forms of SLE cases present similar levels of platelet activation markers, with CD62P correlating with disease activity. Though EVs are not associated with disease activity, the incidence of past thrombotic events is higher in patients with a high level of PS+ REVs.
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Affiliation(s)
- Stephan Hasse
- Axe Maladies Infectieuses et Immunitaires, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
| | - Anne-Sophie Julien
- Département de mathématiques et statistique, Université Laval, Quebec city, Quebec, Canada
| | - Anne-Claire Duchez
- Axe Maladies Infectieuses et Immunitaires, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
| | - Chenqi Zhao
- Axe Maladies Infectieuses et Immunitaires, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
| | - Eric Boilard
- Département de microbiologie-infectiologie et immunologie, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
| | - Paul R Fortin
- Département de Médecine, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
| | - Sylvain G Bourgoin
- Département de microbiologie-infectiologie et immunologie, Centre de recherche du CHU de Québec-Université Laval, Centre ARThrite de l'Université Laval, Quebec city, Quebec, Canada
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Małachowska B, Janikiewicz J, Pietrowska K, Wyka K, Madzio J, Wypyszczak K, Tkaczyk M, Chrul S, Zwiech R, Hogendorf A, Małecki MT, Borowiec M, Krętowski A, Młynarski W, Dobrzyń A, Ciborowski M, Fendler W. Elevated level of lysophosphatidic acid among patients with HNF1B mutations and its role in RCAD syndrome: a multiomic study. Metabolomics 2022; 18:15. [PMID: 35179657 PMCID: PMC8857088 DOI: 10.1007/s11306-022-01873-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/28/2021] [Accepted: 02/01/2022] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Patients with hepatocyte nuclear factor-1 beta (HNF1B) mutations present a variable phenotype with two main symptoms: maturity onset diabetes of the young (MODY) and polycystic kidney disease (PKD). OBJECTIVES Identification of serum metabolites specific for HNF1Bmut and evaluation of their role in disease pathogenesis. METHODS We recruited patients with HNF1Bmut (N = 10), HNF1Amut (N = 10), PKD: non-dialyzed and dialyzed (N = 8 and N = 13); and healthy controls (N = 12). Serum fingerprinting was performed by LC-QTOF-MS. Selected metabolite was validated by ELISA (enzyme-linked immunosorbent assay) measurements and then biologically connected with HNF1B by in silico analysis. HepG2 were stimulated with lysophosphatidic acid (LPA) and HNF1B gene was knocked down (kd) by small interfering RNA. Transcriptomic analysis with microarrays and western blot measurements were performed. RESULTS Serum levels of six metabolites including: arachidonic acid, hydroxyeicosatetraenoic acid, linoleamide and three LPA (18:1, 18:2 and 20:4), had AUC (the area under the curve) > 0.9 (HNF1Bmut vs comparative groups). The increased level of LPA was confirmed by ELISA measurements. In HepG2HNF1Bkd cells LPA stimulation lead to downregulation of many pathways associated with cell cycle, lipid metabolism, and upregulation of steroid hormone metabolism and Wnt signaling. Also, increased intracellular protein level of autotaxin was detected in the cells. GSK-3alpha/beta protein level and its phosphorylated ratio were differentially affected by LPA stimulation in HNF1Bkd and control cells. CONCLUSIONS LPA is elevated in sera of patients with HNF1Bmut. LPA contributes to the pathogenesis of HNF1B-MODY by affecting Wnt/GSK-3 signaling.
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Affiliation(s)
- Beata Małachowska
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215, Lodz, Poland
| | - Justyna Janikiewicz
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology PAS, 3 Pasteur Street, 02-093, Warsaw, Poland
| | - Karolina Pietrowska
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Krystyna Wyka
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Joanna Madzio
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Kamila Wypyszczak
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Marcin Tkaczyk
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, 281/289 Rzgowska Street, 93-338, Lodz, Poland
- Department of Pediatrics Nephrology and Immunology, Medical University of Lodz, 281/289 Rzgowska Street, 93-338, Lodz, Poland
| | - Sławomir Chrul
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, 281/289 Rzgowska Street, 93-338, Lodz, Poland
| | - Rafał Zwiech
- Department of Kidney Transplantation/Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, 22 Kopcinskiego Street, 90-153, Lodz, Poland
| | - Anna Hogendorf
- Department of Pediatrics, Diabetology, Endocrinology, and Nephrology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Maciej T Małecki
- Department of Metabolic Diseases, Medical College, Jagiellonian University, 2 Jakubowskiego Street, 30-688, Cracov, Poland
| | - Maciej Borowiec
- Department of Clinical Genetics, Medical University of Lodz, 251 Pomorska Street, 92-213, Lodz, Poland
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
- Department of Endocrinology, Diabetology, and Internal Medicine, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, 36/50 Sporna Street, 91-738, Lodz, Poland
| | - Agnieszka Dobrzyń
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology PAS, 3 Pasteur Street, 02-093, Warsaw, Poland
| | - Michał Ciborowski
- Clinical Research Centre, Medical University of Bialystok, 24a Sklodowska-Curie Street, 15-276, Bialystok, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 15 Mazowiecka Street, 92-215, Lodz, Poland.
- Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
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Abstract
Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein-coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer.
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Affiliation(s)
- Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; , .,AMED-LEAP, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; , .,AMED-LEAP, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
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Okasato R, Kano K, Kise R, Inoue A, Fukuhara S, Aoki J. An ATX-LPA 6-Gα 13-ROCK axis shapes and maintains caudal vein plexus in zebrafish. iScience 2021; 24:103254. [PMID: 34755093 PMCID: PMC8564058 DOI: 10.1016/j.isci.2021.103254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/26/2021] [Revised: 09/06/2021] [Accepted: 10/08/2021] [Indexed: 12/31/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a potential regulator of vascular formation derived from blood. In this study, we utilized zebrafish as a model organism to monitor the blood vessel formation in detail. Zebrafish mutant of ATX, an LPA-producing enzyme, had a defect in the caudal vein plexus (CVP). Pharmacological inhibition of ATX resulted in a fusion of the delicate vessels in the CVP to form large sac-like vessels. Mutant embryos of LPA6 receptor and downstream Gα13 showed the same phenotype. Administration of OMPT, a stable LPA-analog, induced rapid CVP constriction, which was attenuated significantly in the LPA6 mutant. We also found that blood flow-induced CVP formation was dependent on ATX. The present study demonstrated that the ATX-LPA6 axis acts cooperatively with blood flow and contributes to the formation and maintenance of the CVP by generating contractive force in endothelial cells.
Blocking an ATX-LPA6-Gα13-ROCK axis causes malformation of the caudal vein plexus The axis also contributes to maintaining the fine structure of the caudal vein plexus Activation of LPA6 induces vasoconstriction Caudal vein plexus formation evoked by blood flow is dependent on an ATX-LPA6 axis
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Affiliation(s)
- Ryohei Okasato
- Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan
| | - Ryoji Kise
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan
| | - Shigetomo Fukuhara
- Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.,AMED-LEAP, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan
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Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration. Biomedicines 2021; 9:biomedicines9111727. [PMID: 34829956 PMCID: PMC8615729 DOI: 10.3390/biomedicines9111727] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2021] [Revised: 11/10/2021] [Accepted: 11/17/2021] [Indexed: 12/21/2022] Open
Abstract
Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.
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ENPP2 Methylation in Health and Cancer. Int J Mol Sci 2021; 22:ijms222111958. [PMID: 34769391 PMCID: PMC8585013 DOI: 10.3390/ijms222111958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2021] [Revised: 10/21/2021] [Accepted: 11/01/2021] [Indexed: 11/16/2022] Open
Abstract
Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico the methylation of ENPP2 analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected p-value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased ENPP2 mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of ENPP2 in health and cancer and points out specific DMCs of value as prognostic biomarkers.
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Dehghan M, Shahbazi S, Salehnia M. Effect of Lysophosphatidic Acid on the Vascular Endothelial Growth Factor Expression in Autotransplanted Mouse Ovaries Encapsulated in Sodium Alginate. J Family Reprod Health 2021; 15:91-98. [PMID: 34721597 PMCID: PMC8520664 DOI: 10.18502/jfrh.v15i2.6449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/24/2022] Open
Abstract
Objective: The aim of this study was to evaluate the effect of lysophosphatidic acid (LPA) supplementation during in vitro culture and transplantation of mouse ovaries on the follicular development and expression of vascular endothelial growth factor (VEGF) as an angiogenesis factor at the mRNA and protein levels. Materials and methods: Three weeks old mice ovaries were cultured in the presence and absence of LPA for 24 hours, then they were capsulated in sodium alginate in the presence and absence of LPA as four experimental groups. After transplantation the vaginal smears were performed daily to evaluate the initiation of the estrous cycle. The morphology and follicular distribution were analyzed at the first and fourth estrous cycles using hematoxylin and eosin staining. Then in the groups that showed higher and lower follicular development the immunohistochemistry assay was conducted to identify VEGF protein expression, and the real time RT-PCR was done to analyze the expression of Vegf gene at the first estrus cycle. Results: The large size follicles and also the corpus luteum were prominent in all transplanted groups at fourth estrus cycle in comparison with intact control groups. The statistically lowest percentage of small size follicles and the highest percentages of large size follicles were seen in LPA+/LPA- group (p<0.05). The expression ratio of Vegf to β-actin was significantly higher in this group in comparison with non-LPA treated and intact control groups (p <0.05). Conclusion: LPA as an angiogenesis factor increases the follicular development in transplanted ovaries but it causes early discharge of ovarian reserve.
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Affiliation(s)
- Maryam Dehghan
- Anatomy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shirin Shahbazi
- Medical Genetic Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mojdeh Salehnia
- Anatomy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Liu W, Hopkins AM, Hou J. The development of modulators for lysophosphatidic acid receptors: A comprehensive review. Bioorg Chem 2021; 117:105386. [PMID: 34695732 DOI: 10.1016/j.bioorg.2021.105386] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/11/2021] [Revised: 09/03/2021] [Accepted: 09/25/2021] [Indexed: 12/23/2022]
Abstract
Lysophosphatidic acids (LPAs) are bioactive phospholipids implicated in a wide range of cellular activities that regulate a diverse array of biological functions. They recognize two types of G protein-coupled receptors (LPARs): LPA1-3 receptors and LPA4-6 receptors that belong to the endothelial gene (EDG) family and non-endothelial gene family, respectively. In recent years, the LPA signaling pathway has captured an increasing amount of attention because of its involvement in various diseases, such as idiopathic pulmonary fibrosis, cancers, cardiovascular diseases and neuropathic pain, making it a promising target for drug development. While no drugs targeting LPARs have been approved by the FDA thus far, at least three antagonists have entered phase Ⅱ clinical trials for idiopathic pulmonary fibrosis (BMS-986020 and BMS-986278) and systemic sclerosis (SAR100842), and one radioligand (BMT-136088/18F-BMS-986327) has entered phase Ⅰ clinical trials for positron emission tomography (PET) imaging of idiopathic pulmonary fibrosis. This article provides an extensive review on the current status of ligand development targeting LPA receptors to modulate LPA signaling and their therapeutic potential in various diseases.
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Affiliation(s)
- Wenjie Liu
- Department of Chemistry, Lakehead University and Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada
| | - Austin M Hopkins
- Department of Chemistry, Lakehead University and Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada
| | - Jinqiang Hou
- Department of Chemistry, Lakehead University and Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada.
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Ntatsoulis K, Karampitsakos T, Tsitoura E, Stylianaki EA, Matralis AN, Tzouvelekis A, Antoniou K, Aidinis V. Commonalities Between ARDS, Pulmonary Fibrosis and COVID-19: The Potential of Autotaxin as a Therapeutic Target. Front Immunol 2021; 12:687397. [PMID: 34671341 PMCID: PMC8522582 DOI: 10.3389/fimmu.2021.687397] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2021] [Accepted: 08/13/2021] [Indexed: 12/15/2022] Open
Abstract
Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.
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Affiliation(s)
- Konstantinos Ntatsoulis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Theodoros Karampitsakos
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Eliza Tsitoura
- Laboratory of Molecular & Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Elli-Anna Stylianaki
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Alexios N. Matralis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
| | - Argyrios Tzouvelekis
- Department of Respiratory Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Katerina Antoniou
- Laboratory of Molecular & Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Vassilis Aidinis
- Institute of Bio-Innovation, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
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Gento-Caro Á, Vilches-Herrando E, Portillo F, González-Forero D, Moreno-López B. Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Brain Pathol 2021; 32:e13022. [PMID: 34585475 PMCID: PMC9048519 DOI: 10.1111/bpa.13022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/02/2021] [Revised: 06/19/2021] [Accepted: 09/08/2021] [Indexed: 01/18/2023] Open
Abstract
A preclinical strategy to broaden the search of potentially effective treatments in amyotrophic lateral sclerosis (ALS) relies on identifying factors controlling motor neuron (MN) excitability. These partners might be part of still unknown pathogenic pathways and/or useful for the design of new interventions to affect disease progression. In this framework, the bioactive membrane‐derived phospholipid lysophosphatidic acid (LPA) affects MN excitability through LPA receptor 1 (LPA1). Furthermore, LPA1 knockdown is neuroprotective in transgenic ALS SOD1‐G93A mice. On this basis, we raised the hypothesis that the major LPA‐synthesizing ectoenzyme, autotaxin (ATX), regulates MN excitability and is a potential target to modulate disease development in ALS mice. We show here that PF‐8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME. PF‐8380‐induced alterations were prevented by a small‐interfering RNA directed against mRNA for lpa1. These outcomes support that impact of ATX‐originated lysophospholipids on MN IME engages, at least, the G‐protein‐coupled receptor LPA1. Interestingly, mRNAatx levels increased in the spinal cord of pre‐symptomatic (1–2 months old) SOD1‐G93A mice, thus preceding MN loss. The rise in transcripts levels also occurred in cultured spinal cord MNs from SOD1‐G93A embryos, suggesting that mRNAatx upregulation in MNs is an etiopathogenic event in the ALS cell model. Remarkably, chronic administration in the drinking water of the orally bioavailable ATX inhibitor PF‐8380 delayed MN loss, motor deterioration and prolonged life span in ALS mice. Treatment also led to a reduction in LPA1‐immunoreactive patches in transgenic animals mostly in MNs. These outcomes support that neuroprotective effects of interfering with ATX in SOD1‐G93A mice rely, at least in part, on LPA1 knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology.
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Affiliation(s)
- Ángela Gento-Caro
- GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
| | - Esther Vilches-Herrando
- GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
| | - Federico Portillo
- GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
| | - David González-Forero
- GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
| | - Bernardo Moreno-López
- GRUpo de NEuroDEgeneración y NeurorREparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz-Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
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47
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Zhang C, Li W, Lei X, Xie Z, Qi L, Wang H, Xiao X, Xiao J, Zheng Y, Dong C, Zheng X, Chen S, Chen J, Sun B, Qin J, Zhai Q, Li J, Wei B, Wang J, Wang H. Targeting lysophospholipid acid receptor 1 and ROCK kinases promotes antiviral innate immunity. SCIENCE ADVANCES 2021; 7:eabb5933. [PMID: 34533996 PMCID: PMC8448453 DOI: 10.1126/sciadv.abb5933] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 02/26/2021] [Accepted: 07/29/2021] [Indexed: 06/13/2023]
Abstract
Growing evidence indicates the vital role of lipid metabolites in innate immunity. The lipid lysophosphatidic acid (LPA) concentrations are enhanced in patients upon HCV or SARS-CoV-2 infection, but the function of LPA and its receptors in innate immunity is largely unknown. Here, we found that viral infection promoted the G protein–coupled receptor LPA1 expression, and LPA restrained type I/III interferon production through LPA1. Mechanistically, LPA1 signaling activated ROCK1/2, which phosphorylated IRF3 Ser97 to suppress IRF3 activation. Targeting LPA1 or ROCK in macrophages, fibroblasts, epithelial cells, and LPA1 conditional KO mice promoted interferon-induced clearance of multiple viruses. LPA1 was colocalized with the receptor ACE2 in lung and intestine. Together with previous findings that LPA1 and ROCK1/2 promoted vascular leaking or lung fibrosis, we propose that the current available preclinical drugs targeting the LPA1-ROCK module might protect from SARS-CoV-2 or various virus infections in the intestine or lung.
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Affiliation(s)
- Chi Zhang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Weiyun Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xiaobo Lei
- National Health Commission of the People’s Republic of China, Key Laboratory of System Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhenfei Xie
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Linlin Qi
- State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China
| | - Hui Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Xia Xiao
- National Health Commission of the People’s Republic of China, Key Laboratory of System Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Xiao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuxiao Zheng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Chen Dong
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Xin Zheng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Shiyang Chen
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jianfeng Chen
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Bing Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jun Qin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Qiwei Zhai
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Jinsong Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Bin Wei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China
- College of Life Sciences, Shanghai University, Shanghai 200444, China
- Cancer Center, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jianwei Wang
- National Health Commission of the People’s Republic of China, Key Laboratory of System Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongyan Wang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, Jiangsu 215121, China
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Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells. Int J Mol Sci 2021; 22:ijms221810006. [PMID: 34576169 PMCID: PMC8469279 DOI: 10.3390/ijms221810006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/25/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 12/15/2022] Open
Abstract
Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.
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Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease. Int J Mol Sci 2021; 22:ijms22179575. [PMID: 34502491 PMCID: PMC8431043 DOI: 10.3390/ijms22179575] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/11/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 01/12/2023] Open
Abstract
Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.
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50
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Joshi L, Plastira I, Bernhart E, Reicher H, Triebl A, Köfeler HC, Sattler W. Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model. Int J Mol Sci 2021; 22:8519. [PMID: 34445223 PMCID: PMC8395174 DOI: 10.3390/ijms22168519] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2021] [Revised: 07/29/2021] [Accepted: 08/04/2021] [Indexed: 12/22/2022] Open
Abstract
Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1β, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1β was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.
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Affiliation(s)
- Lisha Joshi
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.)
| | - Ioanna Plastira
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.)
| | - Eva Bernhart
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.)
| | - Helga Reicher
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.)
| | - Alexander Triebl
- Core Facility Mass Spectrometry, Medical University of Graz, 8010 Graz, Austria; (A.T.); (H.C.K.)
| | - Harald C. Köfeler
- Core Facility Mass Spectrometry, Medical University of Graz, 8010 Graz, Austria; (A.T.); (H.C.K.)
- BioTechMed Graz, 8010 Graz, Austria
| | - Wolfgang Sattler
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria; (L.J.); (I.P.); (E.B.); (H.R.)
- BioTechMed Graz, 8010 Graz, Austria
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