DWORF overexpression prevents heart failure in an experimental mouse model of dilated cardiomyopathy

Abstract

Background: Defective intracellular Ca2+ homeostasis is a hallmark feature of heart failure. Increasing the expression level or activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) pump can normalize Ca2+-handling and rescue several genetic and experimental models of heart failure. Results: Our lab has recently identified and characterized a novel transmembrane protein named DWORF (DWarf Open Reading Frame) that binds to SERCA and enhances its activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Transgenic mice with cardiac-specific DWORF over-expression (αMHC-DWORF) have a cellular phenotype that mimics that of PLN KO mice, exhibiting an increase in peak Ca2+-transient amplitude, faster cytosolic Ca2+ decay rates, higher SR Ca2+ load and enhanced cardiomyocyte contractility. Using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to deletion of the muscle-specific LIM protein (MLP KO), other laboratories have previously shown that genetic ablation of PLN leads to a restoration of SERCA activity and prevention of DCM in the hearts of MLP KO mice. Invoking a similar scientific rationale here, we generated αMHC-DWORF Tg/MLP KO mice and observed that DWORF overexpression in the heart of MLP KO mice resulted in a complete rescue of in vivo cardiac function and prevented the pathological remodeling, development of fibrosis and ultrastructural defects that are all characteristic features of MLP KO hearts. At the cellular level, cardiomyocytes isolated from αMHC-DWORF Tg/MLP KO displayed enhanced Ca2+-cycling and contractile properties that contrasted sharply with MLP KO cardiomyocytes, which exhibited depressed contractility. Conclusion: Cardiac-specific over-expression of DWORF prevents the development of the DCM phenotype characteristic of MLP KO mice and provides an attractive candidate for a novel heart failure therapeutic.