从SIRT3调控角度研究病理性心肌肥大过程中能量代谢异常机制

病理性心肌肥大是多种器质性心脏疾病的共同病理变化，线粒体功能障碍导致的能量代谢异常是其重要特征。NAD+依赖性的Ⅲ类组蛋白去乙酰化酶SIRT3是位于线粒体去乙酰化活性最强的SIRTs亚型，通过对多种能量代谢相关酶系去乙酰化修饰调节能量代谢。我们在病理性心肌肥大模型发现SIRT3活性及表达的明显变化，干扰或过表达SIRT3可加剧或抑制心肌肥大反应。本课题拟在此基础上：（1）从整体角度研究从代偿性心肌肥大到心衰过程中SIRT3活性及表达的动态变化过程；（2）通过研究心肌线粒体中SIRT3的限速底物NAD+含量的动态变化以及SIRT3对NAD+合成代谢酶的修饰，探讨SIRT3活性及NAD+生成的交互调控机制；（3）探索影响SIRT3基因转录又与心肌肥大密切相关的上游信号分子。课题主要从SIRT3活性及表达调控角度研究其与病理性心肌肥大的关系，为SIRT3作为病理性心肌肥大干预靶点提供新的理论依据

Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease (OHD), and it is characterized by mitochondrial dysfunction that resulting from disturbed energy metabolism. Among the NAD(+) -dependent histone deacetylases (Sirtuins) in the mitochondrial, SIRT3 exerts the highest deacetylase activity and eventually regulates energy metabolism by deacetylating a variety of energy metabolism enzymes. Our previous studies have demonstrated significant changes of the enzyme activity and the expression of SIRT3 in the in-vitro model of pathological cardiac hypertrophy. Aslo, knockdown and overexpression of SIRT3 in cultured cardiomyocytes could exacerbate and inhibit the cardiac hypertrophic response, respectively. Based on those results, the objectives of this project are to: (1) study the in-vivo dynamic changes of enzyme activity and the expression of SIRT3 during the transition from compensatory cardiac hypertrophy to heart failure; (2) explore the interaction and regulation between the enzyme activity and expression of SIRT3 and the NAD+ production by studying the dynamic changes of NAD+ , which is the cosubstrate of SIRT3, as well as the role of SIRT3 in modification of NAD+ anabolism enzyme; (3) reveal the upstream signaling molecules that not only regulate SIRT3 gene transcription but also highly associated with cardiac hypertrophy. By studying the regulation of activity and expression of SIRT3 during pathological cardiac hypertrophy both in vitro and in vivo, our project will provide a novel theoretical basis for SITR3 as a new target of treatment in patients with pathological cardiac hypertrophy.