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

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.

• Authors: 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
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 284 Issue 2 Pg. C457-74 (Feb 2003) ISSN: 0363-6143 [Print] United States
• PMID: 12388077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cav1 protein, mouse
• Caveolin 1
• Caveolins
• Atrial Natriuretic Factor
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Atrial Natriuretic Factor (genetics)
• Cardiomegaly (enzymology, genetics, pathology)
• Caveolae (metabolism, pathology)
• Caveolin 1
• Caveolins (deficiency, genetics)
• Cell Membrane (genetics, metabolism, pathology)
• Extracellular Matrix (genetics, metabolism, pathology)
• Female
• Fibroblasts (enzymology, pathology)
• Hypertrophy, Left Ventricular (genetics, metabolism, 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, pathology)
• Myocytes, Cardiac (enzymology, pathology)
• Ventricular Dysfunction, Right (genetics, metabolism, pathology)