Lipoprotein-Derived Lysophosphatidic Acid Promotes Atherosclerosis by Releasing CXCL1 from the Endothelium

Abstract

Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments.

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…1 ) confi rm our previous fi nding that adding LPA 18:2 (but not LPA 18:0) to standard mouse chow causes dyslipidemia ( 39 ). Zhou et al ( 26 ) reported that administration of ‫ف‬ 1 g of LPA 20:4 (but not LPA 18:0) by intraperitoneal injection in apoE null mice on a high-fat, high-cholesterol diet accelerated atherosclerosis without signifi cantly altering the dyslipidemia. The data presented here demonstrate that addition of LPA 18:2 (but not LPA 18:0) to standard mouse chow causes dyslipidemia and aortic atherosclerosis in LDLR Ϫ / Ϫ mice similar to that seen on feeding the mice Fig.…”

Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid

“…It is known that oxidized LDL promotes activation of phospholipase D in smooth muscle cells leading to an increase in the production of LPA that stimulates smooth muscle cell proliferation ( 14 ). It is also known that oxidized LDL requires endothelial LPA receptors and autotaxin (phospholipase D) to elicit chemokine (CXC motif) ligand 1 (CXCL1)-dependent monocyte adhesion ( 15 ). In vivo, local and systemic application of unsaturated LPA 20:4 (but not saturated LPA 18:0) (2 nmol twice weekly given by intraperitoneal injection for 4 weeks) accelerated the progression of atherosclerosis in mice without altering blood lipid levels ( 15 ).…”

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

“…In addition, LPA triggers the release of a wide range of proinfl ammatory chemokines such as macro phage infl ammatory protein-1 ␤ , IL-8, eotaxin, and monocyte chemoattractant protein (MCP)-1, which can attract infl ammatory cells to the arterial wall ( 19 ). It is worth noting that LPA progressively accumulates in human and mouse atherosclerotic plaques ( 20,21 ), and was shown to be involved in atherogenesis by virtue of its pro-coagulating capacity ( 20,22 ) and its endothelial/leukocyte inter action ( 23,24 ).…”