Nuclear GAPDH cascade mediates stress-dependent pathological cardiac growth

Abstract

Here we report that stress-induced nuclear translocation of GAPDH mediates heart hypertrophy via Brahma-Related-Gene-1 (BRG1)-associated chromatin remodelling. In response to pressure overload elicited by transverse aortic constriction, we observed nuclear translocation of GAPDH in the mouse heart. We also demonstrated a robust nuclear localization of GAPDH in cardiomyocytes from patients with dilated hypertrophic cardiomyopathy, whereas negligible GAPDH in the nucleus in control subjects. This is the first demonstration of disease-associated nuclear GAPDH directly in living patients. Using immunohistochemical methods and a pharmacological way that selectively blocks GAPDH nuclear translocation (RR compound), we proved the causal involvement of GAPDH cysteine-150 modification in this translocation in Gq-induced cell model for heart hypertrophy. Accordingly, both pharmacological and genetic interventions proved that the same mechanism played a causal role for heart hypertrophy and dysfunction in vivo. We discovered that, upon nuclear translocation, GAPDH augmented the protein interaction of BRG1 and histone deacetylase 2 (HDAC2), which further facilitated the Myh7/Myh6 isoform ratio from the mature to immature status, an essential mechanism for heart hypertrophy. Beyond medical implications, we provide a novel mechanism of stress-induced reversion of a cellular phenotype from adult to fetal state, which is mediated by a "moonlighting" function of GAPDH.