Melatonin enhances atherosclerotic plaque stability by inducing prolyl-4-hydroxylase α1 expression
Melatonin enhances atherosclerotic plaque stability by inducing prolyl-4-hydroxylase α1 expression
复制标题
褪黑素通过诱导脯氨酰 4 羟化酶 α 1 表达增强动脉粥样硬化斑块稳定性
DOI：
10.1097/hjh.0000000000001979
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发表时间：
2019-05-01
影响因子：
4.9
通讯作者：
Zhang, Wencheng
中科院分区：
文献类型：
--
作者：
Li, Hongxuan;Li, Jingyuan;Zhang, Wencheng
目的：褪黑激素是一种主要由松果体分泌的内源性神经激素，具有多种生理功能。然而，其在动脉粥样硬化中的保护作用尚不清楚。在这项研究中，我们试图探讨褪黑激素在调节动脉粥样硬化斑块稳定性载脂蛋白E基因敲除（ApoE（-/-））mimes.Method和结果：平滑肌细胞与褪黑激素，这显着增加的mRNA和蛋白质水平的关键细胞内酶胶原蛋白的成熟和分泌，脯氨酰-4-羟化酶α 1（P4 H α 1）。从机制上讲，褪黑激素增加Akt磷酸化和特异性蛋白1（Sp1）的转录激活，Sp1与P4 H α 1启动子结合，然后诱导P4 H α 1表达。用Akt抑制剂LY 294002或Sp1抑制剂光神霉素A（MTM）预处理可抑制褪黑素诱导的P4 H α 1表达。最后，通过在ApoE（-/-）小鼠的右颈总动脉上放置血管周围项圈来诱导动脉粥样硬化病变，所述小鼠接受或不接受不同剂量的褪黑激素或MTM。高剂量褪黑素通过诱导P4 H α 1的表达增强ApoE（-/-）小鼠体内动脉粥样硬化斑块的稳定性，MTM可逆转P4 H α 1的表达。结论：褪黑素补充治疗动脉粥样硬化可能是一种新的有前景的治疗方法。
Objective: Melatonin, an endogenous neurohormone secreted predominately by the pineal gland, has a variety of physiological functions. However, its protective role in atherosclerosis is not clear. In this study, we sought to investigate the potential effects of melatonin in modulating atherosclerotic plaque stability in apolipoprotein E knockout (ApoE(-/-)) mice.Method and results: Smooth muscle cells were treated with melatonin, which significantly increased mRNA and protein levels of a key intracellular enzyme essential for collagen maturation and secretion, prolyl-4-hydroxylase alpha 1 (P4H alpha 1). Mechanistically, melatonin increased Akt phosphorylation and transcriptional activation of specificity protein 1 (Sp1), which bound with the P4H alpha 1 promoter and then induced P4H alpha 1 expression. Pretreatment with either Akt inhibitor LY294002 or Sp1 inhibitor mithramycin A (MTM) could inhibit melatonin-induced P4H alpha 1 expression. Finally, atherosclerotic lesions were induced by placing a perivascular collar on the right common carotid artery of ApoE(-/-) mice, which were received with or without different doses of melatonin or MTM. High-dose melatonin enhanced atherosclerotic plaque stability in ApoE(-/-) mice in vivo by inducing the expression of P4H alpha 1, which was reversed by MTM.Conclusion: We propose that melatonin supplementation may provide a novel and promising approach to atherosclerosis treatment.