心房钠尿肽通过上调OPA1表达抑制心衰小鼠心肌线粒体分裂并改善心脏功能

ANP Ameliorates Mitochondrial Fragmentation and Cardiac Dysfunction via Upregulation of OPA1 Expression in the Failing Heart

目的:探讨心房钠尿肽(Atrial natriuretic peptide,ANP)对后负荷增加引起的心脏功能下降的保护作用及其机制。方法:选择雄性C57小鼠30只,将其随机分为假手术组(sham)、主动脉弓结扎(Transverse aortic constriction,TAC)手术组和主动脉弓结扎手术ANP干预组(TAC+ANP)。ANP通过皮下注射4周,随后超声检测心脏功能、四腔心切片观察心肌重构,电镜观察心肌线粒体的形态与数量,Western-Blot检测心肌组织中融合分裂相关分子的表达。结果:同sham组相比,TAC组射血分数(Ejection fraction,EF)降低,且左室舒张末内径(End-diastolic left ventricular internal diameter,LVIDd)、左室舒张期后壁厚度(End-diastolic left ventricular posterior wall thickness,LVPWd)、左室质量(LV mass)、心肌质量/胫骨长度(Heart weight/tibial length,HW/TL)显著增加(P<0.05),线粒体面积减小伴数量增加(P<0.05),且线粒体融合相关蛋白OPA1表达量下降(P<0.05)。同TAC组相比,TAC+ANP组EF显著增加,且LVIDd、LV mass、HW/TL均显著下降(P<0.05),线粒体面积增加伴数量减少(P<0.05),且线粒体融合相关蛋白OPA1表达量上调(P<0.05)。在离体培养的心肌细胞中,给予ANP处理可减轻H_2O_2诱导的OPA1表达下降,给与ANP竞争性多肽抑制剂anantin后该作用消失。结论:ANP通过上调OPA1的表达抑制线粒体分裂改善后负荷增加导致的心脏功能下降。

Objective： To explore the protective effect of atrial natriuretic peptide（ANP） on the cardiac dysfunction of pressure overload-induced failing hearts of mice and the underlying mechanisms. Methods： C57 mice（male, 6 weeks） were used for induction of HF through pressure overload. Pressure overload was produced by transverse aortic constriction（TAC）. After surgery, the mice were randomized to given vehicle or ANP for 4 weeks. An in vitro study was performed on cultured cardiomyocytes subjected to control, H2O2,H2O2＋ANP and H_2O_2＋ANP＋anantin. Results： Cardiac ejection fraction（EF） was decreased and myocardial remodeling was significant in response to pressure overload, along with mitochondrial fission which was associated with reduced expression of OPA1 in mice. ANP treatment significantly alleviated myocardial remodeling and improved cardiac function as evidenced by increased left ventricular EF.Importantly, ANP treatment upregulated OPA1 expression and restored mitochondrial morphology in TAC mice. In addition, treatment with ANP also increased OPA1 expression in isolated myocytes under oxidative stress. Conclusion： ANPameliorates mitochondrial fragmentation and cardiac dysfunction via upregulation of OPA1 expression in the failing heart.