Abstract
The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10F/F mice (cFat10−/−). Compared with their wild-type littermates, cFat10−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.
Highlights
Electrical remodeling of cardiac ion channels after myocardial ischemia (MI) plays a vital role in the development of ischemic arrhythmia, which is a major cause of sudden cardiac death[1]
The frequency and mortality of ventricular arrhythmia are increased in ischemic cFat10−/− mice
We previously reported that F-associated transcript 10 (FAT10) protects cardiomyocytes against apoptosis, which is required to maintain cardiac function post-7 day MI15,16
Summary
Electrical remodeling of cardiac ion channels after myocardial ischemia (MI) plays a vital role in the development of ischemic arrhythmia, which is a major cause of sudden cardiac death[1]. Several cardiac ion channels, such as K+, Ca2+, and Na+ channels, participate in susceptibility to cardiac arrhythmias after MI. The main isoform encoded by the Scn5a gene is responsible for the generation of the Na+ current (INa) and is the critical channel for maintaining normal cardiac rhythm[2]. Nav1.5 remodeling provides a critical substrate for the generation of reentrant ventricular arrhythmias in border zones of the infarcted heart[3,4]. Post-translational modification of Nav1.5 is critical for regulating cardiac Na+ channels[5,6]. Nav1.5 is known to undergo Neddylation by
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