The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

Abstract

Purpose of review To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. Recent findings A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. Summary LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

LPA-Induced Thromboxane A2-Mediated Vasoconstriction Is Limited to Poly-Unsaturated Molecular Species in Mouse Aortas

“…Elevation of the generation of unsaturated LPA in the small intestine correlates with the severity of atherosclerosis in in Ldlr−/− mice fed a high-fat diet. This elevation increases the formation of reactive oxygen species and oxidized phospholipids, subsequently raises levels of bacterial lipopolysaccharides, and results in systemic inflammation [26]. LPA also contributes locally to atherosclerosis by promoting the migration inflammatory cells, cytokine secretion, and macrophage transformation [27].…”