Peroxisome proliferator-activated receptor δ 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 unfavorable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we aimed to explore the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidate the underlying mechanisms.

EXPERIMENTAL APPROACH: Plasma levels of PPARδ in patients with acute coronary syndrome (ACS) and stable angina (SA) were measured. SMC contractile and synthetic phenotypic markers, endoplasmic reticulum (ER) stress, and features of atherosclerotic plaque vulnerability were analysed in the brachiocephalic artery of apolipoprotein E-knockout (ApoE-/- ) mice fed a high-cholesterol diet (HCD) and treated with or without PPARδ agonist GW501516. In vitro, the role of PPARδ was elucidated using human aortic SMCs (HASMCs).

KEY RESULTS: Patients with ACS had significantly lower plasma PPARδ 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 PPARδ expression in HASMCs. PPARδ activation inhibited ER stress-induced synthetic phenotype development, ER stress-NLRP3 inflammasome axis activation, and matrix metalloproteinase 2 (MMP2) expression in HASMCs. PPARδ inhibited NFκB signaling and alleviated ER stress-induced SMC phenotypic switching.

CONCLUSIONS AND IMPLICATIONS: Low plasma PPARδ levels may be associated with atherosclerotic plaque vulnerability. Our findings provide new insights into the mechanisms underlying the protective effect of PPARδ on SMC phenotypic switching and improvement the features of atherosclerotic plaque vulnerability.