Peroxisome proliferator-activated receptor delta improves the features of atherosclerotic plaque vulnerability by regulating smooth muscle cell phenotypic switching

Background and Purpose: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARd plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARd in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms.Experimental Approach: Plasma levels of PPARd were measured in patients with acute coronary syndrome (ACS) and stable angina (SA). SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed for the brachiocephalic artery of apolipoprotein E-knockout (ApoE(-/-)) mice, fed a high-cholesterol diet (HCD) and treated with or without the PPARd agonist GW501516. In vitro, the role of PPARd was elucidated using human aortic SMCs (HASMCs).Key Results: Patients with ACS had significantly lower plasma PPARd levels than those with SA. GW501516 reduced atherosclerotic plaque vulnerability, a synthetic SMC phenotype, ER stress markers, and NLRP3 inflammasome expression in HCD-fed ApoE(-/-) mice. ER stress suppressed PPARd expression in HASMCs. PPARd activation inhibited ER stress-induced synthetic phenotype development, ER stress-NLRP3 inflammasome axis activation and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARd inhibited NF?B signalling and alleviated ER stress-induced SMC phenotypic switching.Conclusions and Implications: Low plasma PPARd levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARd on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability.