卵泡抑素抗糖尿病心肌病的作用及其机制研究

Diabetic cardiomyopathy represents the primary cause of heart failure and even death in diabetic patients and up to now there is no specific treatments. Although the underlying pathogenic mechanisms remain incompletely understood, an involvement of fibrosis and altered myocardial energy metabolism have been proposed by comprehensive studies. TGF-β signaling cascades have a well-characterized role in tissue fibrosis and cellular metabolism homeostasis. Follistatin (FST), as an antagonist of TGFβ superfamily members, has strong promise in therapy of fibrosis and significant roles in lipid metabolism. Initial gene therapy preclinical studies performed on non-human primates demonstrated that FST use in clinical settings may be safe. However, its presence and physiological role in heart are just beginning to be understood. Our previous study showed that overexpression of FST remarkably improved cardiac function in diabetic mice model. In this project, we will use cardiac-specific FST transgenic mice and knockout mice and cultured cell to investigate the role of FST against diabetic cardiomyopathy and the underlying mechanisms. In addition, we will assess the feasibility of AAV9-FST with myocardial TnT promotor in the therapy of diabetic cardiomyopathy. The demonstration of the potential benefits of FST on the heart of diabetics by this project may revolutionize current therapeutic approaches for diabetic cardiomyopathy.

糖尿病心肌病是糖尿病患者发展为心衰以及高死亡率的主要原因，其具体机制尚未完全阐明，亦缺乏特异的防治措施。前期研究提示纤维化和能量代谢紊乱在糖尿病心肌病发生发展中扮演重要角色。而TGFβ信号通路与组织纤维化和细胞能量代谢调控关系密切。Follistatin（FST）是多种TGFβ超家族配体的内源性拮抗剂。虽然研究揭示FST具有抗纤维化及调控脂质代谢作用，并在灵长类动物实验中推测其临床应用可能是安全的，但关于FST在心脏方面作用的研究甚少。我们前期研究发现增加FST的表达能显著改善糖尿病小鼠的心功能及胰岛功能。本项目将采用心脏特异性FST基因敲除和转基因小鼠及细胞模型，在体内及体外探讨FST抗糖尿病心肌病的具体作用与机制，尤其是对心肌纤维化和能量代谢异常的影响，并探讨9型腺相关病毒携带的心肌特异性启动子的FST防治糖尿病心肌病的可行性。本研究将为糖尿病心肌病的防治提供重要的理论依据。

糖尿病心肌病(DCM)是糖尿病患者主要的并发症之一，与糖尿病高死亡率密切相关。能量代谢和纤维化在糖尿病心肌病的病理生理过程中发挥关键作用。我们的研究发现，卵泡抑素在糖尿病心肌病中水平降低，而增加卵泡抑素的含量可以保护受损的心功能：一方面卵泡抑素能够减少db鼠心脏中TGFβ成员的水平以及Smad3的磷酸化，并且增加基质金属蛋白酶活性，从而减少胶原沉积，降低糖尿病心肌病中增加的纤维化水平；另一方面，卵泡抑素增加了AKT的磷酸化，使db鼠的心脏发生代偿性增大，并降低ANP、BNP水平，为心脏提供了保护作用；最后，卵泡抑素能够减少心脏中氧化应激的产生，减少脂肪酸的摄取合成以及氧化从而降低心脏脂质毒性，改善糖尿病心肌病的能量代谢障碍。卵泡抑素的上述作用为糖尿病心肌病提供了新的治疗靶点。