Cardiomyocyte-specific skNAC deletion in mice resulted in spontaneous hypertrophy, rapid progression to dilated cardiomyopathy, and increased mortality.
Does skNAC modulate the cardiomyocyte hypertrophic response and preserve cardiac structure and function during pressure overload?
skNAC is essential for maintaining sarcomeric integrity, and its loss drives maladaptive remodeling and heart failure, identifying it as a potential therapeutic target.
Abstract Background Cardiac hypertrophy is initially a compensatory mechanism aimed at maintaining cardiac output, but prolonged pressure overload induces maladaptive remodeling and progressive ventricular dysfunction. The alpha isoform of the muscle-specific nascent polypeptide-associated complex (skNAC) is a post-translational regulator essential for sarcomeric organisation during development. Its contribution to pathological hypertrophy and heart failure in adults has not yet been defined. Purpose We investigated whether skNAC modulates the cardiomyocyte hypertrophic response and preserves cardiac structure and function during pressure overload. Methods skNAC expression and regulation were analysed in neonatal rat ventricular myocytes stimulated with phenylephrine, in mouse models of pressure overload (transverse aortic constriction, TAC and chronic angiotensin II infusion), and in human left ventricular biopsies spanning compensatory to maladaptive remodelling. In vitro studies used siRNA-mediated skNAC knockdown and overexpression. Two cardiomyocyte-specific KO mouse lines (constitutive αMHC-Cre and tamoxifen-inducible αMHC-MerCreMer) were generated and studied at baseline and after pressure overload (TAC conditions). Cardiac phenotype was assessed by echocardiography. skNAC subcellular localisation and function were examined by confocal immunofluorescence and proximity ligation assays. Cardiomyocyte ultrastructure was evaluated by electron microscopy. Results skNAC expression was reduced in cellular, animal and human models of hypertrophy, due to decreased levels of the RNA-binding proteins Rbm24 and Rbm20 that regulate skNAC pre-mRNA splicing. In vitro, skNAC knockdown induced basal cardiomyocyte hypertrophy, whereas its overexpression prevented phenylephrine-induced hypertrophy. Cardiomyocyte-specific skNAC deletion resulted in spontaneous hypertrophy, progressive left ventricular dilatation, severe sarcomere disorganisation, activation of autophagic processes and rapid progression to dilated cardiomyopathy with increased mortality in mice. Finally, skNAC interacted directly with ribosomes, and both are enriched at the Z lines of the sarcomeres. Conclusion skNAC is essential for maintenance of sarcomeric integrity and cardiomyocyte homeostasis. Loss of skNAC expression drives maladaptive remodelling and heart failure, identifying skNAC and its splicing regulators as candidate therapeutic targets to prevent heart failure.
Guilbert et al. (Fri,) conducted a other in Cardiac hypertrophy and heart failure. skNAC deletion or overexpression vs. Wild-type or control conditions was evaluated on Cardiac phenotype, sarcomeric integrity, and mortality. Cardiomyocyte-specific skNAC deletion in mice resulted in spontaneous hypertrophy, rapid progression to dilated cardiomyopathy, and increased mortality.