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Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator–activated receptor delta (PPARδ) 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‐cholesterol diet (HCD)–fed apolipoprotein E knockout (ApoE−/−) 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‐actin 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 PPARδ, but not PPARα and PPARγ, in HCD‐fed ApoE−/− mice. These results were subsequently confirmed in the melatonin‐treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin‐induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ‐mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Beta-blockers are widely used for the treatment of arrhythmia, hypertension, and congestive heart failure. Major trauma causes significant blood loss and subsequent tachycardia and hypotension. Although beta-blockers may induce negative compensatory sympathetic responses to hemorrhagic shock, the effects of beta-blocker use before major trauma on posttrauma outcomes are controversial. Aim: We examined the association between the use of beta-blockers before major trauma and posttrauma outcomes using a nationwide population-based database. Methods: The data for this nationwide population-based retrospective cohort study were obtained from the National Health Insurance Research Database in Taiwan. A total of 2245 beta-blocker users were assigned to the study cohort, and another 8980 patients matched for age, sex, comorbidity, and medication use by inverse probability of treatment weighting formed the comparison cohort. The major outcome assessed was all-cause mortality during a 30-day follow-up period in major trauma patients with or without pretrauma beta-blocker use. Results: Our study included 2245 patients who used beta-blockers before major trauma. Individuals who used beta-blockers did not have a significantly higher cumulative risk of mortality than individuals who did not use beta-blockers (beta-blockers users: 17.19%, nonbeta-blockers users: 16.70%, P = 0.662). Conclusion: Pretrauma beta-blocker users did not have a higher mortality rate after a major trauma even after adjusting for several comorbidities and medications in a nationwide population database. [ABSTRACT FROM AUTHOR]