连接蛋白43在心肌缺血再灌注损伤中的作用及治疗潜力:结构与电-代谢耦联调控视角

The role and therapeutic potential of connexin 43 in myocardial ischemia-reperfusion injury:insights from structural and electro-metabolic coupling regulation

摘要:

连接蛋白43(Cx43)是心肌细胞缝隙连接的基本单位,可介导细胞间电信号传导与代谢耦联,在维持心脏电生理稳定性中发挥关键作用。Cx43的表达、亚细胞定位及功能状态受多种翻译后修饰的调控,包括磷酸化、糖基化、乙酰化、泛素化和S-亚硝基化等。在心肌缺血再灌注损伤过程中,缺血期Cx43去磷酸化引起缝隙连接解耦联,再灌注时氧化应激促进Cx43降解及半通道异常开放,加剧离子失衡、钙超载和氧化损伤,最终导致心律失常和心肌细胞死亡。Cx43在不同亚细胞位置(如线粒体)及特定修饰状态下亦表现出心肌保护潜力。该文系统综述了Cx43的生物学特性与翻译后修饰,评估了其通过调控电-代谢耦联参与心肌缺血再灌注损伤的多重机制,以及作为治疗靶点的应用潜力。

Abstract:

Connexin 43 (Cx43) serves as the fundamental component of gap junctions in cardiomyocytes, facilitating intercellular electrical signal transmission and metabolic coupling. It plays a crucial role in maintaining cardiac electrophysiological stability. The expression, subcellular localization, and functional state of Cx43 are regulated by a variety of post-translational modifications, such as phosphorylation, glycosylation, acetylation, ubiquitination, and S-nitrosylation.During myocardial ischemia-reperfusion injury, Cx43 undergoes dephosphorylation during the ischemic phase, leading to gap junction uncoupling. Upon reperfusion, oxidative stress accelerates Cx43 degradation and induces abnormal opening of hemichannels, thereby exacerbating ion imbalance, calcium overload, and oxidative damage, which ultimately contribute to arrhythmias and cardiomyocyte apoptosis. Moreover, Cx43 exhibits cardioprotective potential under specific subcellular localization (e.g., in mitochondria) and particular modification states. This review systematically summarizes the biological characteristics and post-translational modifications of Cx43, and evaluates its multifaceted mechanisms in myocardial ischemia-reperfusion injury through the regulation of electro-metabolic coupling, as well as its potential as a therapeutic target.