Abstract：
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.
摘要：
易损动脉粥样硬化斑块破裂，致命的动脉粥样硬化血栓事件的主要原因，与全球死亡风险增加有关。过氧化物酶体增殖物激活受体δ（PPARδ）已被证明可以调节血管平滑肌细胞（SMC）表型转换，and,因此，动脉粥样硬化斑块稳定性。据报道，褪黑素在心血管疾病中起着有益的作用；然而，动脉粥样硬化斑块易损性改善的潜在机制尚不清楚.在这项研究中,我们评估了褪黑素在调节SMC表型转换中的作用及其对改善动脉粥样硬化斑块易损性的作用,并探讨了这一过程的潜在机制.我们分析了高胆固醇饮食（HCD）喂养的载脂蛋白E敲除（ApoE-/-）小鼠和人主动脉SMC（HASMC）的动脉粥样硬化斑块易损性特征和SMC表型转变标志物。褪黑素减少动脉粥样硬化斑块大小和坏死核心区域，同时增加胶原含量，纤维帽厚度，平滑肌α-肌动蛋白阳性细胞覆盖在斑块上，这些都是已知的易损斑块的表型特征。在动脉粥样硬化病变中，褪黑素显著降低合成SMC表型和KLF4的表达，增加PPARδ的表达，但不是PPARα和PPARγ，在HCD喂养的ApoE-/-小鼠中。这些结果随后在褪黑激素处理的HASMC中得到证实。使用PPARδ沉默和免疫沉淀测定的进一步分析表明，PPARδ在褪黑激素诱导的SMC表型从合成转换为收缩转换中起作用。总的来说，我们提供了第一个证据表明，褪黑激素通过增强PPARδ介导的SMC表型转换来介导其对斑块失稳的保护作用，从而表明褪黑素治疗动脉粥样硬化的潜力。
