SAHB动态调控SCAD乙酰化修饰在脂肪酸代谢失衡介导房颤的机制研究

Fatty acid metabolic remodeling is involved in the incidence of atrial fibrillation (AF). Our preliminary data showed that short-chain acyl-CoA dehydrogenase(SCAD), one rate-limiting enzyme in fatty acid beta oxidation, was differently decreased in atrial tissues of AF patients, and the level of SCAD acetylation was also significantly increased, suggesting acetylation may be a potential “regulating valve” of cardiac fatty acid metabolism during atrial fibrillation. It has already been identified that stabilized alpha helices of MCL-1 BH3 helix domains(SAHB) played a dynamic regulation role on SCAD acetylation. Accordingly, we put forward the scientific hypothesis that SAHB dynamically regulates SCAD acetylation level in atrial fibrillation, which may affect the fatty acid beta oxidation of atrial cardiomyocytes, leading to metabolic remodeling, thereby promoting the development of atrial fibrillation. In the present project, we will investigate (1) the effect of differential expression and acetylation of SCAD on fatty acid metabolism during AF, and (2) the mechanism of dynamic control of SCAD acetylation by SAHB during AF in both canine model and the primary cardiomyocytes. Our project is expected to clarify the influence of SCAD acetylation on fatty acid metabolic remodeling during AF, providing new targets for the prevention and treatment of AF.

脂肪酸代谢重构参与心房颤动（房颤）发生发展进程。短链酰基辅酶A脱氢酶（SCAD）是肌脂肪酸β氧化的关键限速酶，我们前期研究发现房颤时心房肌SCAD表达显著下调，而其乙酰化水平显著上调，提示乙酰化修饰可能通过影响心房肌能量代谢重构对房颤发生发展中起关键的“调节阀”作用；已知MCL-1蛋白BH3结构域稳定的α螺旋结构（SAHB）可与SCAD特异性结合，并对其乙酰化修饰进行动态调节。据此我们提出科学假说：房颤时SAHB动态调控SCAD乙酰化修饰水平影响心房肌细胞脂肪酸β氧化，导致能量代谢重构，从而促进房颤的发生发展。本项目拟从动物水平和细胞水平（1）研究SCAD在房颤脂肪酸代谢中的功能及乙酰化修饰的调节机制，研究SCAD差异性表达及乙酰化修饰对房颤易感性的影响；（2）深入探讨SAHB动态调控SCAD乙酰化的机制；有望阐明SCAD及其乙酰化修饰对脂肪酸代谢重构的调控机制，为房颤防治提供新靶点。

脂肪酸代谢重构参与心房颤动(房颤)发生发展进程。短链酰基辅酶A脱氢酶(SCAD)是 肌脂肪酸β氧化的关键限速酶，我们前期研究发现房颤时心房肌SCAD表达显著下调，而其乙酰化水平显著上调，提示乙酰化修饰可能通过影响心房肌能量代谢重构对房颤发生发展中起关键 的“调节阀”作用;已知MCL-1蛋白BH3结构域稳定的α螺旋结构(SAHB)可与SCAD特异性结合 ，并对其乙酰化修饰进行动态调节。据此我们提出并验证了科学假说:房颤时SAHB动态调控SCAD乙酰化 修饰水平影响心房肌细胞脂肪酸β氧化，导致能量代谢重构，从而促进房颤的发生发展。本项目从动物水平和细胞水平(1)研究了SCAD在房颤脂肪酸代谢中的功能及乙酰化修饰的调节机 制，研究了SCAD差异性表达及乙酰化修饰对房颤易感性的影响;(2) 外源性补充w-3脂肪酸可通过调控内质网应激降低房颤易感性机制;阐明了SCAD及其乙酰化修饰对脂肪酸代谢重构的调控机制，有望为房颤防治提供新靶点。