GDF11通过调控SIRT1-SMAD2/3信号通路介导糖尿病心肌病心肌纤维化的机制研究

The prognosis of patients suffering from diabetic cardiac fibrosis is poor, and the underlying mechanisms of it remain elusive, which are urgent problems that need to be solved. Our preliminary studies showed that activation of SIRT1 signaling pathway could effectively ameliorate cardiac fibrosis in diabetic hearts, while the upstream and downstream signaling pathways are still unknown. Recent studies published in Science and Cell showed that growth differentiation factor 11 (GDF11) is a novel molecule that plays a key role during the progression of many cardiovascular diseases. Of note, our previous studies confirmed that the expression of GDF11 was significantly increased while the expression of SIRT1 was significantly decreased in diabetic hearts compared with the normal ones, indicating that GDF11 may participate in the development of cardiac fibrosis associated with diabetic comdiomyopathy. Both GDF11 and SIRT1 could affect SMAD2/3 signaling pathway, the key effector molecule that mediates the development of cardiac fibrosis. Therefore, we speculate that GDF11 may promote cardiac fibrosis in diabetic cardiomyopathy through regulating SIRT1-SMAD2/3 signaling pathway. To investigate this issue, gene knockout technology, adenovirus, adeno-associated virus and siRNAs will be used to illuminate the novel mechanism in diabetes induced cardiac fibrosis in vitro and in vivo. In this way, we will provide much more sufficient theoretical basis for new potential pharmacological targets for the prevention and treatment of cardiac fibrosis in diabetic hearts.

糖尿病心肌病所致心肌纤维化预后差，且机制不清，是亟待解决的难题。我们发现：激活SIRT1信号能显著抑制糖尿病心肌病心肌纤维化，但上下游调控通路尚不明确。近来Science、Cell等报道GDF11是对心血管系统发挥重要调控作用的全新关键分子。预实验发现：糖尿病小鼠心脏GDF11表达增高同时伴SIRT1表达降低，提示GDF11可能参与调控糖尿病心肌纤维化。SMAD2/3是糖尿病心肌纤维化关键效应分子，在皮肤等组织研究证实GDF11、SIRT1可调控SMAD2/3表达。因此我们提出：GDF11-SIRT1-SMAD2/3是调控糖尿病心肌病心肌纤维化的新机制。为证实该假说，本项目拟采用基因敲除、腺病毒、腺相关病毒、siRNA干扰等技术，通过在体、离体实验，阐明糖尿病心肌病心肌纤维化的全新分子机制，为寻找最佳治疗方法奠定理论基础。

糖尿病心肌病是糖尿病患者终末期的主要并发症之一，但由于其发病机制复杂，目前临床缺乏有效的治疗药物。生长分化因子11（GDF11）是TGF-β蛋白超家族新成员，在多种心血管疾病中发挥显著的心肌保护作用，然而GDF11是否参与糖尿病心肌病的发生发展及其下游介导的分子机制尚未有研究报道。通过在体和离体实验，我们首次证实心肌过表达GDF11能够抵抗糖尿病小鼠心功能损伤，主要表现在提高抗氧化酶活性并抑制心肌细胞凋亡，减少心肌间质胶原纤维沉积，逆转心功能衰竭的发生。进一步机制研究显示，GDF11显著激活沉默信息调控因子1（SIRT1）信号通路，并上调Nrf2、SOD2蛋白表达，促进Smad2/3去乙酰化。然而，阻断SIRT1信号后，GDF11的上述心肌保护效应被明显削弱。综上我们得出以下结论，GDF11通过激活SIRT1信号通路，减轻心肌组织内氧化应激损伤，抑制心肌细胞凋亡和心肌纤维化，从而逆转糖尿病心肌病理性重构。本研究阐明了GDF11改善糖尿病心肌病的具体分子机制，为临床上防治糖尿病心肌损伤提供了新的理论依据和治疗靶点。

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