Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Atrial Natriuretic Factor / genetics
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Cardiomegaly / enzymology
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Cardiomegaly / genetics*
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Cardiomegaly / pathology
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Caveolae / metabolism
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Caveolae / pathology
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Caveolin 1
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Caveolins / deficiency*
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Caveolins / genetics
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Cell Membrane / genetics
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Cell Membrane / metabolism
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Cell Membrane / pathology
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Extracellular Matrix / genetics*
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Extracellular Matrix / metabolism
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Extracellular Matrix / pathology
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Female
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Fibroblasts / enzymology*
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Fibroblasts / pathology
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Hypertrophy, Left Ventricular / genetics
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Hypertrophy, Left Ventricular / metabolism
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Hypertrophy, Left Ventricular / pathology
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Immunohistochemistry
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Magnetic Resonance Imaging
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Male
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Myocardium / enzymology*
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Myocardium / pathology
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Myocytes, Cardiac / enzymology
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Myocytes, Cardiac / pathology
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Ventricular Dysfunction, Right / genetics
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Ventricular Dysfunction, Right / metabolism
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Ventricular Dysfunction, Right / pathology
Substances
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Cav1 protein, mouse
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Caveolin 1
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Caveolins
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Atrial Natriuretic Factor
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases