心肌纤维化是慢性心衰的特征性病理改变，探寻有效抗纤维化药物并阐明其机制是心衰防治领域的研究热点。我们以往研究首次证实：褪黑素通过抑制心肌纤维化在压力负荷型心衰中发挥保护作用，但具体分子调控机制仍须进一步阐明。RORα是新近发现的褪黑素核受体，SMP30是心肌纤维化的重要调控分子，两者均在心血管疾病中发挥积极作用。预实验发现：褪黑素可激活心衰小鼠心脏RORα，提高SMP30表达。此外，我们在其他疾病模型中证实RORα可能是SMP30的上游信号。SIRT1是介导褪黑素心血管保护作用的关键效应分子，充分证据显示RORα和SMP30均可调节SIRT1表达。因此，我们提出假说：褪黑素通过激活RORα/SMP30并经SIRT1信号通路缓解压力负荷引起的心肌纤维化和心衰。本项目拟采用基因敲除、siRNA干扰等技术，从在体、离体、细胞与分子水平验证上述假说，为临床应用褪黑素治疗压力负荷型心衰奠定理论基础。

Cardiac fibrosis is a characteristic pathological change of chronic heart failure. Finding effective anti-fibrotic drugs and clarifying the underlying mechanisms are the hot topics in the field of heart failure prevention. We first reported that melatonin played a protective role in pressure overload-induced heart failure through inhibiting cardiac fibrosis, but the underlying mechanisms remain elusive. RORα is a newly discovered melatonin nuclear receptor, and SMP30 is an important regulator of cardiac fibrosis. Both RORα and SMP30 play positive roles in treating cardiovascular diseases. Our preliminary study found that melatonin can activate RORα and increase SMP30 expression in heart tissues of heart failure mice. Besides, in other disease model, we preliminarily confirmed that RORα may act as the upstream signal of SMP30. Convincing evidence showed that both RORα and SMP30 can regulate SIRT1, the key effector that mediating melatonin’s cardioprotection. Therefore, we hypothesize that melatonin improves cardiac fibrosis and heart failure caused by pressure overload by activating the SIRT1 signaling pathway in a RORα/SMP30-dependent manner. This project intends to use the techniques of gene knockout and siRNA interference to verify the above hypothesis from the in vivo, ex vivo, cellular and molecular levels, and tries to provide a theoretical basis for the clinical application of melatonin in the treatment of pressure overload-induced heart failure.