Department of Cardiovascular Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing, China.
J Pineal Res. 2020 Sep;69(2):e12666. doi: 10.1111/jpi.12666. Epub 2020 May 23.
Calcific aortic valve disease (CAVD) is highly prevalent with marked morbidity and mortality rates and a lack of pharmaceutical treatment options because its mechanisms are unknown. Melatonin is reported to exert atheroprotective effects. However, whether melatonin protects against aortic valve calcification, a disease whose pathogenesis shares many similarities to that of atherosclerosis, and the underlying molecular mechanisms remain unknown. In this study, we found that the intragastric administration of melatonin for 24 weeks markedly ameliorated aortic valve calcification in high cholesterol diet (HCD)-treated ApoE mice, as evidenced by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased transvalvular peak jet velocity and increased aortic valve area), and decreased osteogenic differentiation marker (Runx2, osteocalcin, and osterix) expression in the aortic valves. Consistent with these in vivo data, we also confirmed the suppression of in vitro calcification by melatonin in hVICs. Mechanistically, melatonin reduced the level of CircRIC3, a procalcification circular RNA, which functions by acting as a miR-204-5p sponge to positively regulate the expression of the procalcification gene dipeptidyl peptidase-4 (DPP4). Furthermore, CircRIC3 overexpression abolished the inhibitory effects of melatonin on hVIC osteogenic differentiation. Taken together, our results suggest that melatonin ameliorates aortic valve calcification via the regulation of CircRIC3/miR-204-5p/DPP4 signaling in hVICs; therefore, melatonin medication might be considered a novel pharmaceutical strategy for CAVD treatment.
钙化性主动脉瓣疾病（CAVD）发病率高，发病率和死亡率高，且缺乏药物治疗选择，因为其发病机制尚不清楚。褪黑素据报道具有抗动脉粥样硬化作用。然而，褪黑素是否能预防主动脉瓣钙化（一种发病机制与动脉粥样硬化有许多相似之处的疾病）以及潜在的分子机制尚不清楚。在这项研究中，我们发现，24 周的褪黑素胃内给药可显著改善高胆固醇饮食（HCD）处理的 ApoE 小鼠的主动脉瓣钙化，这表现在主动脉瓣叶片厚度和钙沉积减少，超声心动图参数改善（跨瓣峰值射流速度降低，主动脉瓣面积增加），以及主动脉瓣中成骨分化标志物（Runx2、骨钙素和osterix）表达降低。与这些体内数据一致，我们还证实了褪黑素在 hVICs 中抑制体外钙化。从机制上讲，褪黑素降低了 CircRIC3 的水平，CircRIC3 是一种促钙化的环状 RNA，其作用是作为 miR-204-5p 的海绵，正向调节促钙化基因二肽基肽酶-4（DPP4）的表达。此外，CircRIC3 的过表达消除了褪黑素对 hVIC 成骨分化的抑制作用。总之，我们的结果表明，褪黑素通过调节 hVIC 中的 CircRIC3/miR-204-5p/DPP4 信号通路改善主动脉瓣钙化；因此，褪黑素药物治疗可能被认为是 CAVD 治疗的一种新的药物策略。
