Targeting the autotaxin - Lysophosphatidic acid receptor axis in cardiovascular diseases

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 extracellular LPA is produced locally by the secreted lysophospholipase D, autotaxin (ATX), through its binding to various beta 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.