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PMID:12388077
Citation |
Cohen, AW, Park, DS, Woodman, SE, Williams, TM, Chandra, M, Shirani, J, Pereira de Souza, A, Kitsis, RN, Russell, RG, Weiss, LM, Tang, B, Jelicks, LA, Factor, SM, Shtutin, V, Tanowitz, HB and Lisanti, MP (2003) Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts. Am. J. Physiol., Cell Physiol. 284:C457-74 |
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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. |
Links |
PubMed Online version:10.1152/ajpcell.00380.2002 |
Keywords |
Animals; Atrial Natriuretic Factor/genetics; Cardiomegaly/enzymology; Cardiomegaly/genetics; Cardiomegaly/pathology; Caveolae/metabolism; Caveolae/pathology; Caveolin 1; Caveolins/deficiency; Caveolins/genetics; Cell Membrane/genetics; Cell Membrane/metabolism; Cell Membrane/pathology; Extracellular Matrix/genetics; Extracellular Matrix/metabolism; Extracellular Matrix/pathology; Female; Fibroblasts/enzymology; Fibroblasts/pathology; Hypertrophy, Left Ventricular/genetics; Hypertrophy, Left Ventricular/metabolism; Hypertrophy, Left Ventricular/pathology; Immunohistochemistry; Magnetic Resonance Imaging; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases/metabolism; Myocardium/enzymology; Myocardium/pathology; Myocytes, Cardiac/enzymology; Myocytes, Cardiac/pathology; Ventricular Dysfunction, Right/genetics; Ventricular Dysfunction, Right/metabolism; Ventricular Dysfunction, Right/pathology |
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