Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts.
Recently, development of a caveolin-1-deficient (Cav-1 null) mouse model has allowed the detailed analysis of caveolin-1's function in the context of a whole animal. Interestingly, we now report that the hearts of Cav-1 null mice are markedly abnormal, despite the fact that caveolin-1 is not expressed in cardiac myocytes. However, caveolin-1 is abundantly expressed in the nonmyocytic cells of the heart, i.e., cardiac fibroblasts and endothelia. Quantitative imaging studies of Cav-1 null hearts demonstrate a significantly enlarged right ventricular cavity and a thickened left ventricular wall with decreased systolic function. Histological analysis reveals myocyte hypertrophy with interstitial/perivascular fibrosis. Because caveolin-1 is thought to act as a negative regulator of the p42/44 MAP kinase cascade, we performed Western blot analysis with phospho-specific antibodies that only recognize activated ERK1/2. As predicted, the p42/44 MAP kinase cascade is hyperactivated in Cav-1 null heart tissue (i.e., interstitial fibrotic lesions) and isolated cardiac fibroblasts. In addition, endothelial and inducible nitric oxide synthase levels are dramatically upregulated. Thus loss of caveolin-1 expression drives p42/44 MAP kinase activation and cardiac hypertrophy.
Cohen
Alex W
AW
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Park
David S
DS
Woodman
Scott E
SE
Williams
Terrence M
TM
Chandra
Madhulika
M
Shirani
Jamshid
J
Pereira de Souza
Andrea
A
Kitsis
Richard N
RN
Russell
Robert G
RG
Weiss
Louis M
LM
Tang
Baiyu
B
Jelicks
Linda A
LA
Factor
Stephen M
SM
Shtutin
Vitaliy
V
Tanowitz
Herbert B
HB
Lisanti
Michael P
MP
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D021941:Caveolae / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000172:deficiency* / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; 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*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D009320:Atrial Natriuretic Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases