A Secreted Phospholipase A2 Induces Formation of Smooth Muscle Foam Cells Which Transdifferentiate to Macrophage-Like State

Abstract

Vascular smooth muscle cells (VSMCs) loaded with lipid droplets (LDs) are markers of atherosclerosis. In this disease, inflammatory Group IIA-secreted phospholipase A2s (GIIA sPLA2s) are highly expressed in VSMCs, but their actions in these cells are unknown. Here, we investigated the ability of myotoxin III (MT-III), an ophidian GIIA sPLA2 sharing structural and functional features with mammalian GIIA sPLA2s, to induce LD formation and lipid metabolism factors involved in this effect. Modulation of VSMC phenotypes by this sPLA2 was also evaluated. Incubation of VSMCs with MT-III significantly increased the number of LDs. MT-III upregulated scavenger receptor type 1 (SR-A1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein expression and enhanced acetylated-low density lipoprotein (acLDL) uptake by VSMCs, revealing the ability of a GIIA PLA2 to modulate scavenger receptor activities. MT-III induced translocation and protein expression of PPAR-γ and -β/δ. Inhibition of peroxisome proliferator-activated receptors (PPARs) and diacylglycerol O-acyltransferase (DGAT) and acyl-CoA:cholesterolacyltransferase (ACAT) enzymes abrogated MT-III-induced LD formation. Moreover, in response to MT-III, VSMCs acquired phagocytic activity and expressed macrophage markers CD68 and MAC-2. In conclusion, MT-III is able to stimulate VSMCs and recruit factors involved in lipid uptake and metabolism, leading to the formation of VSMC-derived foam cells with acquisition of macrophage-like markers and functions.

Inflammatory Effects of Bothrops Phospholipases A2: Mechanisms Involved in Biosynthesis of Lipid Mediators and Lipid Accumulation

“…In line with the ability of svPLA 2 s to elicit an inflammatory response characterized by a high level of inflammatory mediators and free fatty acids, it was demonstrated that MT-III (Asp49 PLA 2 ), isolated from B. asper venom, induced LD formation enriched by PLIN2 protein in mice peritoneal macrophages [170]. This effect was likewise observed in rat vascular smooth muscle cells isolated from the thoracic aorta stimulated by MT-III [168]. Moreover, the ability of MT-II, a Lys49 PLA 2 homologue devoid of catalytic activity from B. asper venom, to directly activate macrophages to form LDs was reported [167].…”

Phospholipase A2 group IIA correlates with circulating high-density lipoprotein cholesterol and modulates cholesterol efflux possibly through regulation of PPAR-γ/LXR-α/ABCA1 in macrophages

“…It has been confirmed that, in macrophages, PPAR-γ and LXR-α controlled the cholesterol removal through the modulation of ABCA1 [ 25 ]. Karina and colleagues revealed that, myotoxin III (an ophidian GIIA sPLA2) increased PPAR-γ and ABCA1 expression, and was involved in the lipid metabolism [ 28 ]. Consistently, our results indicated that sPLA2-IIA might increase the expression of ABCA1 through PPAR-γ/LXR-α pathway in THP-1 cells, and subsequently augment the cholesterol efflux capacity of cells.…”

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

“…14,15 Accordingly, targeting ClC-3 could be employed as a potential therapeutic strategy for AS, at least in part, by regulating JNK/p38 MAPK-dependent SRa expression and foam cell formation (Figure 3). 77…”