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 genetically engineered mice deficient for either alpha-sarcoglycan (Sgca) or delta-sarcoglycan (Sgcd). We found that only Sgcd null mice developed cardiomyopathy with focal areas of necrosis as the histological hallmark in cardiac and skeletal muscle. Absence of the sarcoglycan-sarcospan (SG-SSPN) complex in skeletal and cardiac membranes was observed in both animal models. Loss of vascular smooth muscle SG-SSPN complex was only detected in Sgcd null mice and associated with irregularities of the coronary vasculature. Administration of a vascular smooth muscle relaxant prevented onset of myocardial necrosis. Our data indicate that disruption of the SG-SSPN complex in vascular smooth muscle perturbs vascular function, which initiates cardiomyopathy and exacerbates muscular dystrophy.
Coral-Vazquez
R
R
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City 52242, USA.
Cohn
R D
RD
Moore
S A
SA
Hill
J A
JA
Weiss
R M
RM
Davisson
R L
RL
Straub
V
V
Barresi
R
R
Bansal
D
D
Hrstka
R F
RF
Williamson
R
R
Campbell
K P
KP
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology*; D003331:Coronary Vessels / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009363:Neoplasm Proteins; D010805:Physical Conditioning, Animal / Q000009:adverse effects; D049031:Sarcoglycans
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D049031:Sarcoglycans; C491632:Sspn protein, mouse