Atherosclerotic Lesion Progression Changes Lysophosphatidic Acid Homeostasis to Favor its Accumulation

Abstract

Lysophosphatidic acid (LPA) accumulates in the central atheroma of human atherosclerotic plaques and is the primary platelet-activating lipid constituent of plaques. Here, we investigated the enzymatic regulation of LPA homeostasis in atherosclerotic lesions at various stages of disease progression. Atherosclerotic lesions were induced in carotid arteries of low-density lipoprotein receptor-deficient mice by semiconstrictive collar placement. At 2-week intervals after collar placement, lipids and RNA were extracted from the vessel segments carrying the plaque. Enzymaticand liquid chromatography-mass spectrometry-based lipid profiling revealed progressive accumulation of LPA species in atherosclerotic tissue preceded by an increase in lysophosphatidylcholine, a precursor in LPA synthesis. Plaque expression of LPA-generating enzymes cytoplasmic phospholipase A 2 IVA (cPLA 2 IVA) and calcium-independent PLA 2 VIA (iPLA 2 VIA) was gradually increased, whereas that of the LPA-hydrolyzing enzyme LPA acyltransferase ␣ was quenched. Increased expression of cPLA 2 IVA and iPLA 2 VIA in advanced lesions was confirmed by immunohistochemistry. Moreover, LPA receptors 1 and 2 were 50% decreased and sevenfold upregulated, respectively. Therefore, key proteins in LPA homeostasis are increasingly dysregulated in the plaque during atherogenesis, favoring intracellular LPA production. This might at least partly explain the observed progressive accumulation of this thrombogenic proinflammatory lipid in human and mouse plaques. Thus, intervention in the enzymatic LPA production may be an attractive measure to lower intraplaque LPA content, thereby reducing plaque progression and thrombogenicity. (Am J

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

“…We and others have previously demonstrated that LPA progressively accumulates in plaques during disease progression ( 20,21 ) and we here confi rmed the presence and actual location of a range of LPA species in the atherosclerotic Fig. 3.…”

“…During the development of atherosclerosis, tissue concentrations of LPA increase ( 21 ), thus enhancing local bioavailability of LPA with the capacity to destabilize plaques. Apoptosis at later stages of disease progression is considered deleterious for plaque stability ( 30 ).…”

“…One of oxLDL's main lipid constituents, LPA, has a wide range of effects on mast cells, infl uencing processes such as proliferation, differentiation, and release of histamine, macrophage infl ammatory protein-1 ␤ , IL-8, eotaxin, and MCP-1 ( 18,19 ). Moreover, as this bioactive lipid progressively accumulates in plaques during disease progression ( 20,21 ), it may be a likely candidate for vascular mast cell activation in the context of atherosclerosis.…”

“…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 ).…”

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

“…In basic studies, for example, LysoPA causes the migration of smooth muscle cells and activated platelets, while S1P increases the integrity of blood vessels, protects epithelial cells and macrophages from apoptosis and induces eNOS in epithelial cells. In clinical studies, LysoPA has been found to be abundant in the lipid core region of human atherosclerotic plaques 6,7) . Additionally, the plasma LysoPA levels are higher in patients with acute coronary syndrome 8) , whereas the plasma S1P levels and HDL-linked S1P levels are lower in those with ischemic heart disease.…”