Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle:A novel mechanism for cardiomyopathy and muscular dystrophy

To investigate mechanisms in the pathogenesis of cardiomyopathy associated with mutations of the dystrophin-glycoprotein complex, we analyzed genetica lly engineered mice deficient for either alpha-sarcoglycan (Sgca) or delta- sarcoglycan (Sgcd). We found that only Sgcd null mice developed cardiomyopa thy with focal areas of necrosis as the histological hallmark in cardiac an d skeletal muscle. Absence of the sarcoglycan-sarcospan (SG-SSPN) complex i n skeletal and cardiac membranes was observed in both animal models. Loss o f vascular smooth muscle SG-SSPN complex was only detected in Sgcd null mic e and associated with irregularities of the coronary vasculature. Administr ation of a vascular smooth muscle relaxant prevented onset of myocardial ne crosis. Our data indicate that disruption of the SG-SSPN complex in vascula r smooth muscle perturbs vascular function, which initiates cardiomyopathy and exacerbates muscular dystrophy.