4E-BP inhibition ameliorates heart failure through translational upregulation of SERCA2a and modulation of mitochondrial redox signaling in cardiomyocytes.

Abstract

Reduced SERCA2a expression impairs cardiomyocyte contraction and relaxation, contributing to the progression of congestive heart failure (CHF). The translation of specific mRNAs, including SERCA2a, is suppressed by 4E-binding proteins (4E-BPs) through preventing the assembly of an intact initiation complex. Here, we investigated the role of 4E-BPs in regulating cardiac SERCA2a expression and transverse aortic constriction (TAC)-induced CHF in mice via genetic deletion of both 4E-BP1 and 4E-BP2 (4E-BP1/2 DKO), as well as through cardiac-specific knockdown or overexpression of 4E-BP1. 4E-BP1/2 DKO markedly alleviated TAC-induced CHF and mortality without affecting left ventricular hypertrophy. RNA-seq and mitochondrial respiratory analyses showed that 4E-BP1/2 DKO mitigated TAC-induced mitochondrial dysfunction and oxidative stress. Similar protective effects were observed with 4E-BP1 knockdown, whereas 4E-BP1 overexpression worsened these pathological changes. Mechanistically, 4E-BP1/2 DKO increased SERCA2a mRNA binding to eIF4G, thereby enhancing SERCA2a protein translation in the myocardium. Cardiac-specific Serca2a knockdown in TAC-challenged 4E-BP1/2 DKO mice reversed these protective effects. Consistent findings were obtained in a cardiomyocyte cell line. In summary, our results demonstrated that 4E-BP1/2 DKO translationally increased myocardial SERCA2a expression and rescued mice from CHF development after TAC, indicating that interventions reducing the signaling of cardiac 4E-BPs may be a novel therapeutic approach for treating CHF.