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

Author:

Lien Chih‐Feng1,Lin Chin‐Sheng1ORCID,Shyue Song‐Kun2,Hsieh Po‐Shiuan34,Chen Sy‐Jou5,Lin Yi‐Tan4,Chien Shu6,Tsai Min‐Chien4ORCID

Affiliation:

1. Division of Cardiology, Department of Medicine Tri‐Service General Hospital, National Defense Medical Center Taipei Taiwan

2. Cardiovascular Division Institute of Biomedical Sciences, Academia Sinica Taipei Taiwan

3. Graduate Institute of Medical Science National Defense Medical Center Taipei Taiwan

4. Department of Physiology and Biophysics, Graduate Institute of Physiology National Defense Medical Center Taipei Taiwan

5. Department of Emergency Medicine Tri‐Service General Hospital, National Defense Medical Center Taipei Taiwan

6. Department of Bioengineering and Medicine, Institute of Engineering in Medicine University of California San Diego La Jolla California USA

Abstract

Background and PurposeVascular 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 ApproachPlasma 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 ResultsPatients 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 ImplicationsLow 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.

Funder

Ministry of Science and Technology, Taiwan

Tri-Service General Hospital

Publisher

Wiley

Subject

Pharmacology

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