硫化氢巯基化修饰自噬相关蛋白Atg4及大蒜有机硫化合物在心衰及心肌重塑中的作用及机制

Chronic heart failure, the final step of different cardiovascular diseases (CVD), remains the leading cause of cardiovascular death without a cure. We and others have demonstrated that hydrogen sulfide (H2S) signals, act as an endogenous regulator in maladaptive myocardial remodeling and dysfunction. Moreover, a growing body of evidence has indicated that H2S signals may contribute to the established health benefits of many dietary components in the cardiovascular system. Thus, H2S signals appears to be an attractive drug target for the treatment of heart failure. However, our preliminary results revealed that H2S-regulating enzyme (CSE) deficiency may contribute to the progression of cardiac dysfunction in a setting of chronic pressure overload. At a molecular level, we found that chronic pressure overload appears to maximally activate autophagy with decreased autophagic flux in the heart. In addition, CSE deficiency suppressed autophagic protein ATG4 expression in the pressure overloaded heart. Collectively, we hypothesize that H2S signals contributing to pathological cardiac remodeling and dysfunction when myocardial autophagy is impaired. To test the hypothesis, we will apply gene gain- and loss-of-function approaches in combination with pharmacological and genetic regulation of autophagy to address the role of H2S-autophagy axis in maladaptive cardiac hypertrophy and heart failure in a setting of myocardial autophagy impairment. The outcome will not only shed light on a hormetic nature of H2S in the heart, but also provide novel perspectives to the rational design and development of natural drugs of H2S donors for the treatment of cardiovascular diseases.

在心力衰竭发展过程中，心肌重塑的失代偿是其重要的危险因素，但人们对起关键作用的靶点分子的认识还十分有限。近年来，硫化氢（H2S）在调节心脏内环境稳定中的重要作用引起我们关注，但其具体作用机制研究尚不明确。我们的前期研究结果显示：①H2S缺失参与慢性压力负荷引起的心功能不全的发展，②并伴随自噬功能损伤。据此我们提出假说：H2S通过调节自噬功能，参与压力负荷引起的心脏肥大和心衰。为验证该假说，我们将采用体内/外基因功能获得或缺失以及药理学的手段，进一步阐明不同自噬背景下，H2S通过二硫键水解修饰自噬相关蛋白ATG4，调控自噬，干预心肌细胞中线粒体的功能及能量代谢，从而影响心衰及心肌重塑。本研究将深入揭示H2S信号在心衰和心肌重塑过程中的具体作用机制；并结合天然有机硫药物的应用，为治疗心血管疾病药物的开发提供线索。

在心衰发病病理过程中，H2S信号在压力负荷下的心肌重塑过程发挥了关键作用。本研究揭示H2S信号对心衰的调控作用与自噬功能状态紧密相关，自噬功能障碍可能是介导H2S信号在心脏失代偿性重塑和功能失常的主要原因。通过Cth基因体内/外过表达和敲低技术，建立主动脉弓缩窄术（TAC）模型和心肌细胞肥大模型，表明H2S在是应激状态下减轻活性氧的产生，尤其是通过维持自噬活性减轻线粒体氧化应激；其机制是通过修饰自噬相关蛋白ATG4发生作用的，从而调控线粒体功能与心肌能量代谢，最终影响心脏疾病的发展与转归。本研究将为临床药物干预H2S信号通路治疗心脏疾病提供新的理论基础，也将有助于开发新型天然的H2S供体及释放制剂。项目已发表文章1篇，待发表2篇。培养研究生2名，其中一名硕士生已经取得学位。项目获得经费资助21万元，支出19.320747万元，剩余经费计划用于本项目后续研究支出及论文版面费。