0271: Conditional ablation of ShcA induces heart failure through dysfunctional neuregulin and dystrophin signaling

Abstract

ShcA is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation. We used the Cre-loxP technology and the smooth muscle protein-22 (Sm22) cre transgene, to ablate ShcA specifically in the cardiovascular system from early embryonic development. Conditionally mutant mice developed signs of severe dilated cardiomyopathy, myocardial infarctions, and premature death. No evidence of a vascular contribution to the phenotype was observed. Histological analysis of the heart reveals aberrant intercalated z-disk and M-band structures, and misalignments of T-tubules with z-disk. We find that the neuregulin-1-ErbB3 signaling and the baroreceptor reflex response, which have been functionally associated, are both altered in the mutant mice. We further demonstrate that ShcA interacts with Cav-1 and the costameric protein plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA), and that its deletion leads to abnormal dystrophin signaling. Our studies demonstrate that ShcA modulates ErbB3/Neuregulin and Cav-1/dystrophin signaling, two crucial pathways for z-disk and costamere linkages in cardiomyocytes.