{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:43:17Z","timestamp":1790109797057,"version":"4.0.1"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T00:00:00Z","timestamp":1720483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator\u2013activated receptor delta (PPAR\u03b4) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high\u2010cholesterol diet (HCD)\u2013fed apolipoprotein E knockout (<jats:italic>ApoE<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha\u2010actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPAR\u03b4, but not PPAR\u03b1 and PPAR\u03b3, in HCD\u2010fed <jats:italic>ApoE<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. These results were subsequently confirmed in the melatonin\u2010treated HASMCs. Further analysis using PPAR\u03b4 silencing and immunoprecipitation assays revealed that PPAR\u03b4 plays a role in the melatonin\u2010induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPAR\u03b4\u2010mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis.<\/jats:p>","DOI":"10.1111\/jpi.12988","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T06:19:33Z","timestamp":1720592373000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Melatonin Ameliorates Atherosclerotic Plaque Vulnerability by Regulating PPAR\u03b4\u2010Associated Smooth Muscle Cell Phenotypic Switching"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2105-7570","authenticated-orcid":false,"given":"Sy\u2010Jou","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Tri\u2010Service General Hospital National Defense Medical Center  Taipei 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