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Articles in PresS, published online ahead of print October 9, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00380.2002
Submitted on August 22, 2002
Accepted on October 3, 2002
1 Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Hormone-dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, NY, USA
2 Cardiology and Infectious Disease, Albert Einstein College of Medicine, Bronx, NY, USA
3 Cardiology and Infectious Disease, Albert Einstein College of Medicine, Bronx, NY, USA; Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
4 Physiology & Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA
5 Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
* To whom correspondence should be addressed. E-mail: lisanti{at}aecom.yu.edu.
Caveolin-1 is expressed primarily in fibroblasts and endothelial cells, where it serves as the principal structural component of caveolae. Recently, the development of a caveolin-1 (Cav-1) null mouse model has allowed the detailed analysis caveolin-1's function in the context of a whole animal in vivo. Interestingly, we now report that the hearts of Cav-1 null mice are markedly abnormal, despite the fact that caveolin-1 is not normally expressed in cardiac myocytes. However, caveolin-1 is abundantly expressed in the non-myocytic cells of the heart, i.e., cardiac fibroblasts and endothelial cells. In Cav-1 null mice, gated MRI shows a significantly enlarged right ventricular cavity and a thickened left ventricular wall. Furthermore, functional studies using transthoracic echocardiography demonstrate concentric left ventricular hypertrophy and decreased systolic function. Consistent with MRI and echocardiography, histological analysis reveals myocyte hypertrophy with enlarged and double nuclei, interstitial/perivascular fibrosis, as well as myocyte degeneration. Northern blot analysis of the ventricles shows a dramatic upregulation of atrial natriuretic factor (ANF) mRNA, which is characteristic of cardiac hypertrophy. As 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 hyper-activated in Cav-1 null heart tissue. Immuno-staining of cardiac frozen sections localized activated ERK1/2 to areas of interstitial fibrosis that contain cardiac fibroblasts. In support of this notion, cultures of isolated Cav-1 (-/-) cardiac fibroblasts also demonstrated hyper-activation of ERK1/2. In addition, further immunoblot analysis of cardiac tissue revealed that eNOS and iNOS are dramatically upregulated, while the levels of caveolin-3, cyclin D1, GLUT4, and PKC
remain unchanged. Thus, it appears that loss of caveolin-1 expression in cardiac fibroblasts leads to p42/44 MAP kinase activation and interstitial fibrosis, driving the development of cardiac hypertrophy and cardiomyopathy.
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