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

Br J Pharmacol. 2023 Aug;180(16):2085-2101. doi: 10.1111/bph.16074. Epub 2023 Apr 5.

Abstract

Background and purpose: Vascular smooth muscle cells (SMCs) undergo phenotypic switching during sustained inflammation, contributing to an unfavourable atherosclerotic plaque phenotype. PPARδ plays an important role in regulating SMC functions; however, its role in atherosclerotic plaque vulnerability remains unclear. Here, we explored the pathological roles of PPARδ in atherosclerotic plaque vulnerability in severe atherosclerosis and elucidated the underlying mechanisms.

Experimental approach: Plasma levels of PPARδ 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 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 signalling 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.

Keywords: PPARδ; acute coronary syndrome; atherosclerotic plaque vulnerability; endoplasmic reticulum stress; phenotypic switching; smooth muscle cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • PPAR delta* / genetics
  • Phenotype
  • Plaque, Atherosclerotic* / metabolism

Substances

  • Apolipoproteins E
  • GW 501516
  • Inflammasomes
  • Matrix Metalloproteinase 2
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • PPAR delta
  • Ppard protein, mouse
  • PPARD protein, human