CARM1/Clock/NAMPT调控NAD+代谢在能量代谢重构介导增龄性房颤的机制研究

增龄是房颤的独立危险因素，增龄性房颤的发病机制尚不明确；衰老的过程中烟酰胺腺嘌呤二核苷（NAD+）水平及其限速酶烟酰胺磷酸核糖转移酶（NAMPT）表达下降；节律因子（Clock）是NAMPT的转录因子，而组蛋白精氨酸甲基转移酶（CARM1）调控Clock的转录活性。本研究组前期研究发现在房颤心耳中CARM 1表达上调而NAMPT下调，据此科学假说：在衰老过程中， CARM 1与Clock相互作用并调控NAMPT的表达和功能，通过调节线粒体Sirtuins酶活性和代谢相关酶的乙酰化和琥珀酰化水平，导致心肌能量代谢重构，促进增龄性房颤的发生发展。本研究拟构建NAMPT及CARMR 1过表达/低表达病毒，在犬房颤模型和原代心肌细胞研究：①NAMPT表达对NAD+代谢和房颤易感性的影响，② 探讨CARMR 1/Clock/NAMPT 调控心肌能量代谢的分子机制；为增龄性房颤防治寻找新的干预靶点。

Aging is an independent risk factor for atrial fibrillation (AF), and the pathogenesis of aging-related atrial fibrillation is not clear. During aging, the level of NAD+ and the expression of rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) decreases. The clock is a transcription factor of NAMPT while histone arginine methyltransferase (CARM1) regulate transcription activity of Clock. In the preliminary study, we found that the expression of CARM1 was up-regulated and the expression of NAMPT was down-regulated in atrial fibrillation. Thus, we suppose that: CARM1 interacts with Clock to regulates the expression and function of NAMPT during aging, further to regulate the activity of Sirtuins in mitochondria which affect the acetylation and succinylation level of metabolic enzymes. All of these changes may ultimately lead to remodeling of myocardial energy metabolism and promotes the development of aging AF. In this project, we will construct NAMPT overexpression / low expression virus and CARMR1 overexpression / low expression virus to investigate the effect of NAMPT expression on NAD + metabolism and AF susceptibility. Moreover, the mechanism of CARMR1 / Clock / NAMPT regulating myocardial energy metabolism will be defined in the canine model and primary cardiac myocyte, which may contribute to new theoretical basis and therapeutic targets for aging-related AF prevention and treatment.