Lysophospholipids and their G protein-coupled receptors in atherosclerosis

Abstract

Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates such as membrane phospholipids (PLs) and sphingolipids (SLs). They play a major role as extracellular mediators by activating G-protein coupled receptors (GPCRs) and stimulating diverse cellular responses from their signaling pathways. LPLs are involved in various pathologies of the vasculature system including coronary heart disease and hypertension. Many studies suggest the importance of LPLs in their association with the development of atherosclerosis, a chronic and severe vascular disease. This paper focuses on the pathophysiological effects of different lysophospholipids on atherosclerosis, which may promote the pathogenesis of myocardial infarction and strokes. Their atherogenic biological activities take place in vascular endothelial cells, vascular smooth muscle cells, fibroblasts, monocytes and macrophages, dendritic cells, T-lymphocytes, platelets, etc.

Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation

“…Strikingly, all of the detected LPC species were significantly induced in the aortas of ApoE −/− mice, with the exception of linoleoyl-LPC (18:2) ( Figure 1A) . LPC is produced by the enzymatic action of phospholipase A 2 (PLA 2 ) on phosphatidylcholine; and the PLA 2 superfamily enzyme members are critically involved in atherosclerosis 11, 22 . For these reasons, we also examined the gene expression changes of all the PLA 2 superfamily enzymes between ApoE −/− mice and WT mice using microarray analysis.…”

“…Collectively, we and others have demonstrated a critical proatherogenic role for mtROS in EC activation during early atherosclerosis. Notably, LPC could also activate macrophages besides promoting EC activation 11 and diminishing mtROS in macrophages reduced lesion development in atherosclerotic mice 40 . Further study is needed to determine the role of LPC-induced mtROS in lesional macrophages during the development of atherosclerosis.…”

“…Although controversies exist regarding what the real LPC receptor(s) is in the cell, LPC has been shown to stimulate cytosolic Ca 2+ in different cell types 11 . In addition, it has been shown that LPC induced cellular Ca 2+ uptake from an extracellular source via transient receptor potential vanilloid 2 (TRPV2) channel 43 .…”

“…Lysophosphatidylcholines (LPCs) are a group of proinflammatory lipids, which are critically involved in the pathogenesis of atherosclerosis 11 . Multiple lines of evidence indicate that aortic LPCs are induced in advanced atherosclerosis.…”

Lysophospholipid Receptors, as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation—Novel Paradigm and Therapeutic Potential

“…For this study we used the endogenous metabolite lysophospholipids (LPLs) and its receptors as the prototype. LPLs are bioactive, lipid-derived metabolites that act through G-protein coupled receptors (GPCRs) to either serve as signaling molecules at physiological concentrations that control cellular homeostasis or as inflammatory regulators at elevated concentrations [17]. LPLs are generated by regiospecific phospholipases on substrates such as membrane phospholipids and sphingolipids.…”