Centre de Recherche du Centre Hospitalier Universitaire de Québec - Université Laval, Canada; Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V4G2, Canada.
Centre de Recherche du Centre Hospitalier Universitaire de Québec - Université Laval, Canada.
Biochem Pharmacol. 2019 Jun;164:74-81. doi: 10.1016/j.bcp.2019.03.035. Epub 2019 Mar 27.
Lysophosphatidic acid (LPA) is a well-characterized bioactive lipid mediator, which is involved in development, physiology, and pathological processes of the cardiovascular system. LPA can be produced both inside cells and in biological fluids. The majority of extracellularLPAis produced locally by the secreted lysophospholipase D, autotaxin (ATX), through its binding to various β integrins or heparin sulfate on cell surface and hydrolyzing various lysophospholipids. LPA initiates cellular signalling pathways upon binding to and activation of its G protein-coupled receptors (LPA1-6). LPA has potent effects on various blood cells and vascular cells involved in the development of cardiovascular diseases such as atherosclerosis and aortic valve sclerosis. LPA signalling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, as well as angiogenesis. For instance, LPA promotes activation and aggregation of platelets through LPA5, increases expression of adhesion molecules in endothelial cells, and enhances expression of tissue factor in vascular smooth muscle cells. Furthermore, LPA induces differentiation of monocytes into macrophages and stimulates oxidized low-density lipoproteins (oxLDLs) uptake by macrophages to form foam cells during formation of atherosclerotic lesions through LPA1-3. This review summarizes recent findings of the roles played by ATX, LPA and LPA receptors (LPARs) in atherosclerosis and calcific aortic valve disease. Targeting the ATX-LPAR axis may have potential applications for treatment of patients suffering from various cardiovascular diseases.
溶血磷脂酸（LPA）是一种特征明确的生物活性脂质介质，参与心血管系统的发育、生理和病理过程。LPA 既可以在细胞内产生，也可以在生物体液中产生。大多数细胞外 LPA 是由分泌型溶脂酶 D（lysophospholipase D，LPLD）即自分泌运动因子（autotaxin，ATX）通过与其细胞表面的各种β整合素或硫酸乙酰肝素结合，并水解各种溶脂磷脂而局部产生的。LPA 通过与 G 蛋白偶联受体（LPA1-6）结合并激活这些受体，引发细胞信号通路。LPA 对参与动脉粥样硬化和主动脉瓣硬化等心血管疾病发展的各种血细胞和血管细胞具有强大的作用。LPA 信号通路可驱动细胞迁移和增殖、细胞因子产生、血栓形成、纤维化以及血管生成。例如，LPA 通过 LPA5 促进血小板的激活和聚集，增加内皮细胞中黏附分子的表达，并增强血管平滑肌细胞中组织因子的表达。此外，LPA 通过 LPA1-3 诱导单核细胞向巨噬细胞分化，并刺激巨噬细胞摄取氧化型低密度脂蛋白（oxLDL），从而在动脉粥样硬化病变形成过程中形成泡沫细胞。本综述总结了 ATX、LPA 和 LPA 受体（LPAR）在动脉粥样硬化和钙化性主动脉瓣疾病中的作用的最新发现。靶向 ATX-LPAR 轴可能为治疗各种心血管疾病患者提供潜在的应用。
