Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
J Pineal Res. 2020 Aug;69(1):e12661. doi: 10.1111/jpi.12661. Epub 2020 May 27.
Melatonin functions as an endogenous protective molecule in multiple vascular diseases, whereas its effects on thoracic aortic aneurysm and dissection (TAAD) and underlying mechanisms have not been reported. In this study, TAAD mouse model was successfully induced by β-aminopropionitrile fumarate (BAPN). We found that melatonin treatment remarkably prevented the deterioration of TAAD, evidenced by decreased incidence, ameliorated aneurysmal dilation and vascular stiffness, improved aortic morphology, and inhibited elastin degradation, macrophage infiltration, and matrix metalloproteinase expression. Moreover, melatonin blunted oxidative stress damage and vascular smooth muscle cell (VSMC) loss. Notably, BAPN induced a decrease in SIRT1 expression and activity of mouse aorta, whereas melatonin treatment reversed it. Further mechanistic study demonstrated that blocking SIRT1 signaling partially inhibited these beneficial effects of melatonin on TAAD. Additionally, the melatonin receptor was involved in this phenomenon. Our study is the first to report that melatonin exerts therapeutic effects against TAAD by reducing oxidative stress and VSMC loss via activation of SIRT1 signaling in a receptor-dependent manner, thus suggesting a novel therapeutic strategy for TAAD.
褪黑素作为一种内源性保护分子，在多种血管疾病中发挥作用，但其对胸主动脉瘤和夹层（TAAD）的作用及其潜在机制尚未报道。在这项研究中，成功地通过丁烯二腈富马酸盐（BAPN）诱导 TAAD 小鼠模型。我们发现褪黑素治疗显著地防止了 TAAD 的恶化，表现为发病率降低、动脉瘤扩张和血管僵硬程度改善、主动脉形态改善、弹性蛋白降解、巨噬细胞浸润和基质金属蛋白酶表达减少。此外，褪黑素减轻了氧化应激损伤和血管平滑肌细胞（VSMC）的丢失。值得注意的是，BAPN 诱导小鼠主动脉中 SIRT1 表达和活性降低，而褪黑素治疗则逆转了这一现象。进一步的机制研究表明，阻断 SIRT1 信号通路部分抑制了褪黑素对 TAAD 的这些有益作用。此外，褪黑素受体也参与了这一现象。我们的研究首次报道，褪黑素通过激活 SIRT1 信号通路，以受体依赖的方式减轻氧化应激和 VSMC 丢失，从而发挥对 TAAD 的治疗作用，为 TAAD 提供了一种新的治疗策略。
