Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts

Alex W. Cohen, David S. Park, Scott E. Woodman, Terrence M. Williams, Madhulika Chandra, Jamshid Shirani, Andrea Pereira De Souza, Richard N. Kitsis, Robert G. Russell, Louis M. Weiss, Baiyu Tang, Linda A. Jelicks, Stephen M. Factor, Vitaliy Shtutin, Herbert B. Tanowitz, Michael P. Lisanti

Research output: Contribution to journalArticle

195 Scopus citations

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 phosphospecific 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.

Original languageEnglish (US)
Pages (from-to)C457-C474
JournalAmerican Journal of Physiology - Cell Physiology
Volume284
Issue number2 53-2
StatePublished - Feb 1 2003

Keywords

  • Cardiac fibroblasts
  • Cardiomyopathy
  • Caveolae
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Cohen, A. W., Park, D. S., Woodman, S. E., Williams, T. M., Chandra, M., Shirani, J., De Souza, A. P., Kitsis, R. N., Russell, R. G., Weiss, L. M., Tang, B., Jelicks, L. A., Factor, S. M., Shtutin, V., Tanowitz, H. B., & Lisanti, M. P. (2003). Caveolin-1 null mice develop cardiac hypertrophy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts. American Journal of Physiology - Cell Physiology, 284(2 53-2), C457-C474.