Lysophosphatidic Acid and Cardiovascular Disease Risk

溶血磷脂酸与心血管疾病风险

• 批准号: 10614416
• 负责人: ANDREW J MORRIS
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614416
• 关键词: Acceleration; Adipose tissue; Aging; Aortic Valve Stenosis; Apolipoproteins; Atherosclerosis; Behavioral; Binding; Cardiovascular Diseases; Cardiovascular Models; Cell Culture System; Cell Differentiation process; Cell Surface Receptors; Cell surface; Cells; Coronary Arteriosclerosis; Data; Development; Diagnosis; Diet; Disease; Down-Regulation; Elderly; Endothelial Cells; Endothelium; Environmental Risk Factor; Enzymes; Exhibits; Experimental Models; Fibrosis; Funding; Gene Knock-Out Model; Gene Silencing; General Population; Generations; Genes; Genetic; Genetic Transcription; Heart; Heart Diseases; Heart Valves; Heritability; Human; Incidence; Inflammation; Inflammatory; Injury; Intervention; Investigational Therapies; LPAR4 gene; Link; Lipids; Lipoprotein (a); Literature; Low-Density Lipoproteins; Lysophosphatidic Acid Receptors; Mediating; Medical; Metabolic Diseases; Modeling; Molecular; Mus; NF-kappa B; Normal tissue morphology; Pathologic; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Process; Reagent; Receptor Activation; Recombinants; Reporting; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Source; Stenosis; Stress; Testing; Therapeutic Intervention; Tissues; Variant; Vascular calcification; Veterans; antagonist; aortic valve; aortic valve disorder; blood pump; bone; calcification; cardiovascular disorder risk; cell type; disorder risk; drug efficacy; experimental study; extracellular; genetic risk factor; heart cell; immune cell infiltrate; improved; inhibitor; interest; interstitial cell; lipid phosphate phosphatase; lysophosphatidic acid; military veteran; mineralization; mortality; mouse model; novel strategies; osteogenic; particle; permissiveness; pharmacologic; prevent; promoter; receptor; response; small molecule; small molecule therapeutics; tissue culture; transcription factor; valve replacement; vascular inflammation; Acceleration; Adipose tissue; Aging; Aortic Valve Stenosis; Apolipoproteins; Atherosclerosis; Behavioral; Binding; Cardiovascular Diseases; Cardiovascular Models; Cell Culture System; Cell Differentiation process; Cell Surface Receptors; Cell surface; Cells; Coronary Arteriosclerosis; Data; Development; Diagnosis; Diet; Disease; Down-Regulation; Elderly; Endothelial Cells; Endothelium; Environmental Risk Factor; Enzymes; Exhibits; Experimental Models; Fibrosis; Funding; Gene Knock-Out Model; Gene Silencing; General Population; Generations; Genes; Genetic; Genetic Transcription; Heart; Heart Diseases; Heart Valves; Heritability; Human; Incidence; Inflammation; Inflammatory; Injury; Intervention; Investigational Therapies; LPAR4 gene; Link; Lipids; Lipoprotein (a); Literature; Low-Density Lipoproteins; Lysophosphatidic Acid Receptors; Mediating; Medical; Metabolic Diseases; Modeling; Molecular; Mus; NF-kappa B; Normal tissue morphology; Pathologic; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Process; Reagent; Receptor Activation; Recombinants; Reporting; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Source; Stenosis; Stress; Testing; Therapeutic Intervention; Tissues; Variant; Vascular calcification; Veterans; antagonist; aortic valve; aortic valve disorder; blood pump; bone; calcification; cardiovascular disorder risk; cell type; disorder risk; drug efficacy; experimental study; extracellular; genetic risk factor; heart cell; immune cell infiltrate; improved; inhibitor; interest; interstitial cell; lipid phosphate phosphatase; lysophosphatidic acid; military veteran; mineralization; mortality; mouse model; novel strategies; osteogenic; particle; permissiveness; pharmacologic; prevent; promoter; receptor; response; small molecule; small molecule therapeutics; tissue culture; transcription factor; valve replacement; vascular inflammation

Veterans have a higher incidence of cardiovascular disease than the general population. Valvular diseases including Calcific Aortic Valve Disease (CAVD) are a particular concern for the aging Veteran Population. At present, there is no medical therapy to delay or reverse CAVD, and the only treatment is valve replacement for severe aortic valve stenosis. CAVD involves remodeling of the heart valve tissue as a consequence of endothelial injury, immune cell infiltration and myofibroblastic / osteogenic differentiation of cells that can ultimately result in valve leaflet thickening and profound calcification. The fibrosis and calcification stiffen the leaflets and can result in leaflet fusion that reduces valve opening and causes valve stenosis. Understanding the molecular mechanisms that drive these changes might lead to the development of much needed therapies for CAVD. In the past funding period we made mouse models to study the roles of a bioactive lipid, lysophosphatidic acid (LPA) in cardiovascular and metabolic disease processes. In the course of these studies we found that mice deficient in the enzyme autotaxin (ATX) that generates LPA were protected from valve calcification and thickening in a commonly used experimental model. We also observed that mice lacking the enzyme lipid phosphate phosphatase 3 (LPP3) that can inactivate LPA exhibited greater valve calcification in this model. These findings are likely translatable to humans because LPP3 levels are decreased during development of human CAVD while ATX accumulates in the valve tissue and ATX binds to lipoprotein (a) particles which are themselves associated with CAVD risk. Valvular Interstitial Cells (VICs) are resident cells of the heart valve tissue that are normally responsible for maintaining the integrity of the heart valves. Pathological differentiation of these cells to myofibroblastic and osteogenic phenotypes is central to the development of CAVD. Consistent with literature reports, our preliminary data shows that mouse and human VICs express LPA selective cell surface receptors. Differentiation of these cells to an osteogenic phenotype and subsequent calcification can be readily observed in culture medium containing serum which is a rich source of LPA. Pharmacological antagonism of LPA receptors blocks osteogenic differentiation and calcification of these cells in culture. In the past funding period we characterized transcriptional circuits that regulate LPP3 expression to understand why expression is increased in inflammation and decreased by heritable variants that associate with increased coronary artery disease risk. These studies provide reagents and a framework for understanding why LPP3 expression is decreased in CAVD. Here we propose to test the broad hypothesis that LPA signaling promotes CAVD. We will test this hypothesis by using mouse models with cell and tissue type selective inactivation of LPA receptors, LPP3 and ATX to identify the cell and tissue types involved the permissive effect of LPA on CAVD with a particular interest in the possibility that secreted ATX and cell surface LPP3 could have non cell autonomous effects on this process. As an orthogonal approach, we will use well characterized experimental therapeutics (ATX inhibitors and LPA receptor antagonists) to validate results from these gene knockout models and evaluate their potential for pharmacological intervention in CAVD. Studies in mouse models will be augmented by experiments using cultured mouse and human VICs where again cells with genetic deficiencies or treatment with small molecule therapeutics can be used to define the role of LPA signaling in osteogenic differentiation and calcification. We will also examine how LPP3 expression is regulated during these processes and test specific hypotheses about why LPP3 expression is decreased during development of CAVD. This research will provide important new information about a pharmacologically tractable lipid signaling pathway that appears to be central to the development of CAVD. This information could lead to new approaches for non- surgical management of CAVD in Veterans.

与普通人群相比，退伍军人的心血管疾病发生率更高。瓣膜疾病 包括钙化主动脉瓣疾病（CAVD）特别关注老化的老年人群。在 目前，没有延迟或反向CAVD的药物疗法，唯一的治疗方法是替换瓣膜 严重的主动脉瓣狭窄。 CAVD涉及重塑心脏瓣膜组织 内皮损伤，免疫细胞浸润和肌成纤维细胞 /成骨分化，可以 最终导致瓣膜小叶增厚和深刻的钙化。纤维化和钙化使 传单并可能导致传单融合，从而减少瓣膜开口并导致瓣膜狭窄。理解 推动这些变化的分子机制可能导致急需疗法的发展 对于cavd。在过去的资金期间，我们制作了小鼠模型来研究生物活性脂质的作用， 心血管和代谢疾病过程中的溶血磷酸酸（LPA）。在这些研究过程中 我们发现，在生成LPA的酶自动肝素（ATX）中缺乏小鼠免受瓣膜的影响 在常用的实验模型中钙化和增厚。我们还观察到缺乏的小鼠 脂质磷酸磷酸磷酸磷酸酶3（LPP3），可灭活LPA在钙化中表现出更大的瓣膜钙化 这个模型。这些发现可能可以转换为人类，因为LPP3水平在 人Cavd的发展，而ATX积聚在瓣膜组织中，ATX与脂蛋白结合（a） 与CAVD风险相关的颗粒。瓣膜间质细胞（VIC）是驻留细胞 通常负责维持心脏瓣膜完整性的心脏瓣膜组织。病理 这些细胞与肌纤维细胞和成骨表型的分化对于发展至关重要 cavd。与文献报告一致，我们的初步数据表明，小鼠和人类VIC表达LPA 选择性细胞表面受体。这些细胞的分化为成骨表型和随后的 钙化可以很容易地在含有丰富LPA来源的培养基中观察到。 LPA受体的药理拮抗作用阻断了这些细胞的成骨分化和钙化 在文化中。在过去的资金期间，我们表征了调节LPP3表达为的转录电路 了解为什么与与之相关的遗传变体的炎症中表达会增加 冠状动脉疾病风险增加。这些研究提供了试剂和框架，以理解为什么 在CAVD中LPP3表达降低。在这里，我们建议测试LPA信号传导的广泛假设 促进CAVD。我们将通过将小鼠模型与细胞和组织类型选择性选择进行检验 LPA受体，LPP3和ATX的失活以识别涉及允许效应的细胞和组织类型 在CAVD上的LPA，对分泌的ATX和细胞表面LPP3的可能性特别感兴趣 对此过程的非细胞自主影响。作为一种正交的方法，我们将使用良好的特征 实验疗法（ATX抑制剂和LPA受体拮抗剂）以验证这些基因的结果 敲除模型并评估其在CAVD中的药理干预潜力。小鼠研究 使用培养的小鼠和人类维克斯的实验将增强模型，其中再次具有遗传的细胞 小分子疗法的缺陷或治疗可以用于定义LPA信号在 成骨分化和钙化。我们还将检查在这些过程中如何调节LPP3的表达 过程和检验特定假设，说明为何在CAVD发育过程中LPP3表达降低。 这项研究将提供有关药理学上可拖动的脂质信号通路的重要新信息 这似乎是CAVD发展的核心。这些信息可能会导致非 - 退伍军人的CAVD手术管理。