title: 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.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Cohen
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Madhulika
authors.initials: M
authors.lastname: Chandra
authors.forename: Jamshid
authors.initials: J
authors.lastname: Shirani
authors.forename: Andrea
authors.initials: A
authors.lastname: Pereira de Souza
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.forename: Robert G
authors.initials: RG
authors.lastname: Russell
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.forename: Baiyu
authors.initials: B
authors.lastname: Tang
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jelicks
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Factor
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Shtutin
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D021941:Caveolae / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000172:deficiency* / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D009320:Atrial Natriuretic Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases