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。瓣膜病 包括钙化性主动脉瓣疾病（CAVD）在内的疾病是老年退伍军人群体特别关心的问题。在 目前，没有药物治疗来延迟或逆转CAVD，唯一的治疗方法是瓣膜置换术， 主动脉瓣重度狭窄CAVD涉及心脏瓣膜组织的重塑， 内皮损伤、免疫细胞浸润和细胞的肌纤维母细胞/成骨分化， 最终导致瓣叶增厚和严重钙化。纤维化和钙化覆盖了 瓣叶的扩张会导致瓣叶融合，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治疗方法的发展 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。在这些研究的过程中 我们发现，缺乏产生LPA的自分泌运动因子（ATX）的小鼠可以免受瓣膜感染 钙化和增厚在常用的实验模型。我们还观察到， 能够抑制LPA的脂质磷酸磷酸酶3（LPP3）在 该模型这些发现很可能适用于人类，因为LPP3水平在哺乳期内降低。 当ATX在瓣膜组织中积累并且ATX结合脂蛋白（a）时， 这些颗粒本身与CAVD风险有关。瓣膜间质细胞（VIC）是心脏瓣膜的常驻细胞。 通常负责维持心脏瓣膜完整性的心脏瓣膜组织。病理 这些细胞分化成肌纤维母细胞和成骨表型是骨形成的核心。 CAVD。与文献报道一致，我们的初步数据显示小鼠和人VIC表达LPA， 选择性细胞表面受体。这些细胞分化为成骨表型， 在含有血清的培养基中可以容易地观察到钙化，血清是LPA的丰富来源。 LPA受体的药理学拮抗作用阻断了这些细胞的成骨分化和钙化 在文化中。在过去的资助期间，我们描述了调节LPP3表达的转录回路， 理解为什么表达在炎症中增加，而在与炎症相关的遗传变异中减少。 增加冠状动脉疾病风险。这些研究提供了试剂和框架来理解为什么 LPP3在CAVD中表达降低。在这里，我们提出测试广泛的假设，LPA信号 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验证这一假设。 LPA受体、LPP3和ATX的失活以鉴定涉及容许效应的细胞和组织类型 LPA对CAVD的影响，特别感兴趣的是分泌的ATX和细胞表面LPP 3可能具有 非细胞自主的影响。作为一种正交方法，我们将使用充分表征的 实验治疗（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中的药理学干预潜力。小鼠研究 将通过使用培养的小鼠和人类VIC的实验来增强模型，其中再次具有遗传学特性的细胞 缺乏或用小分子治疗剂治疗可用于定义LPA信号传导在 成骨分化和钙化。我们还将研究LPP3的表达是如何调节在这些过程中， 过程和测试关于为什么LPP3表达在CAVD的发展过程中减少的特定假设。 这项研究将提供重要的新信息，一个易处理的脂质信号通路 这似乎是CAVD发展的核心。这些信息可能会导致新的方法，为非- 退伍军人CAVD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