Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade.
A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane micro-domains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (-/-) knock-out mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, alpha-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.
Department of Molecular Pharmacology, Division of Hormone-Dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Scott E
SE
Woodman
David S
DS
Park
Alex W
AW
Cohen
Michelle W-C
MW
Cheung
Madhulika
M
Chandra
Jamshid
J
Shirani
Baiyu
B
Tang
Linda A
LA
Jelicks
Richard N
RN
Kitsis
George J
GJ
Christ
Stephen M
SM
Factor
Herbert B
HB
Tanowitz
Michael P
MP
Lisanti
D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics*; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics* / Q000502:physiology*; D002458:Cell Fractionation; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D004452:Echocardiography; D004789:Enzyme Activation; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D049031:Sarcoglycans
C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049031:Sarcoglycans; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases