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

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.

退伍军人的心血管疾病发病率高于普通人群。瓣膜疾病 包括钙化性主动脉瓣疾病 (CAVD) 是老龄化退伍军人特别关注的问题。在 目前，尚无药物治疗可以延迟或逆转 CAVD，唯一的治疗方法是瓣膜置换术。 严重的主动脉瓣狭窄。 CAVD 涉及心脏瓣膜组织的重塑，这是由于 内皮损伤、免疫细胞浸润和细胞的肌纤维细胞/成骨分化 最终导致瓣叶增厚和深度钙化。纤维化和钙化使组织变硬 瓣叶并可能导致瓣叶融合，从而减少瓣膜开口并导致瓣膜狭窄。理解 驱动这些变化的分子机制可能会导致急需的疗法的开发 对于 CAVD。在过去的资助期间，我们制作了小鼠模型来研究生物活性脂质的作用， 溶血磷脂酸（LPA）在心血管和代谢疾病过程中的作用。在这些研究过程中 我们发现，缺乏产生 LPA 的自分泌运动因子 (ATX) 的小鼠受到瓣膜保护 常用实验模型中的钙化和增厚。我们还观察到缺乏 可以灭活 LPA 的酶脂质磷酸磷酸酶 3 (LPP3) 在 这个模型。这些发现很可能适用于人类，因为 LPP3 水平在 人类 CAVD 的发展，同时 ATX 在瓣膜组织中积聚并且 ATX 与脂蛋白结合 (a) 本身与 CAVD 风险相关的颗粒。瓣膜间质细胞 (VIC) 是常驻细胞 通常负责维持心脏瓣膜完整性的心脏瓣膜组织。病理性的 这些细胞向肌纤维母细胞和成骨表型的分化对于 CAVD。与文献报道一致，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。这些细胞分化为成骨表型以及随后的 在含有富含 LPA 的血清的培养基中可以很容易地观察到钙化。 LPA 受体的药理学拮抗作用阻止这些细胞的成骨分化和钙化 在文化中。在过去的资助期间，我们对调节 LPP3 表达的转录电路进行了表征 了解为什么表达在炎症中增加并因与相关的遗传变异而减少 增加冠状动脉疾病的风险。这些研究提供了试剂和框架来理解为什么 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。我们将通过使用具有细胞和组织类型选择性的小鼠模型来检验这一假设 LPA 受体、LPP3 和 ATX 失活，以识别涉及许可效应的细胞和组织类型 LPA 对 CAVD 的影响特别令人感兴趣的是分泌的 ATX 和细胞表面 LPP3 可能具有 对此过程的非细胞自主效应。作为一种正交方法，我们将使用特征良好的 实验疗法（ATX抑制剂和LPA受体拮抗剂）来验证这些基因的结果 敲除模型并评估其药物干预 CAVD 的潜力。小鼠研究 模型将通过使用培养的小鼠和人类 VIC 的实验得到增强，其中细胞又具有遗传性 缺陷或小分子疗法治疗可用于定义 LPA 信号传导在 成骨分化和钙化。我们还将研究在这些过程中 LPP3 表达是如何调节的。 过程并测试关于为什么 LPP3 表达在 CAVD 发展过程中减少的具体假设。 这项研究将提供有关药理学上易于处理的脂质信号通路的重要新信息 这似乎是 CAVD 发展的核心。这些信息可能会为非 退伍军人 CAVD 的外科治疗。

项目成果

Myeloid-Specific Deletion of Lipid Plpp3 (Phosphate Phosphatase 3) Increases Cardiac Inflammation After Myocardial Infarction.

脂质 Plpp3（磷酸酯磷酸酶 3）的髓系特异性缺失会增加心肌梗死后的心脏炎症。

• DOI: 10.1161/atvbaha.122.317830
• 发表时间: 2023
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Tripathi,Himi;Shindo,Kazuhiro;Donahue,RenéeR;Gao,Erhe;Kuppa,Annapurna;ElKammar,Mahmoud;Morris,AndrewJ;Smyth,SusanS;Abdel-Latif,Ahmed
• 通讯作者: Abdel-Latif,Ahmed

Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.

• DOI: 10.3390/cancers15112937
• 发表时间: 2023-05-26
• 期刊: Cancers
• 影响因子: 5.2

Antibodies Against Lysophosphatidic Acid Protect Against Blast-Induced Ocular Injuries.

• DOI: 10.3389/fneur.2020.611816
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Arun P;Rossetti F;DeMar JC;Wang Y;Batuure AB;Wilder DM;Gist ID;Morris AJ;Sabbadini RA;Long JB
• 通讯作者: Long JB