title: Caveolin-1 modulates TGF-β1 signaling in cardiac remodeling.
abstract: The cardiac response to myocardial injury includes fibrotic and hypertrophic processes and a key mediator in this response is transforming growth factor-β1 (TGF-β1). Caveolin-1 (cav1), the main structural protein of caveolae, is an inhibitor of the TGF-β1 signaling pathway. To examine the role of cav1 in cardiac repair, cav1 deficient (Cav1(-/-)) and wild type (WT) mice were subjected to cryoinjury of the left ventricle (LV). At baseline the two groups exhibited no inflammation, similar collagen content, and similar cardiac function. After injury, Cav1(-/-) animals displayed enhanced TGF-β1 signaling, as reflected by a 3-fold increase in the activation of the Smad2-dependent pathway and more widespread collagen deposition in the heart. Qualitative and quantitative analyses indicated that collagen deposition peaked in the WT LV 14days after injury, accompanied by increased mRNA abundance for procol1a2 (2-fold) and procol3a1 (3-fold). Collagen deposition was further enhanced in Cav1(-/-) mice, which was accompanied by reduced expression of matrix metalloproteinases MMP-8 (3-fold) and -13 mRNA (2-fold). The levels of expression of inflammatory markers of acute phase were similar between the strains However, macrophage clearance in the damaged region was delayed in Cav1(-/-) mice. We observed a 4-fold decrease in collagen deposition in Cav1(-/-) mice injected with a cav1 scaffolding domain peptide (CSD) and a 2-fold decrease in WT mice treated with the CSD. We conclude that cav1 has a direct role in reducing TGF-β1 signaling and as such might be an appropriate target for therapies to influence cardiac remodeling.
authors.affiliation: Dept. of Cell and Molecular Biology, University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA. skmiyasa@hawaii.edu
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Miyasato
authors.forename: Jorik
authors.initials: J
authors.lastname: Loeffler
authors.forename: Ralph
authors.initials: R
authors.lastname: Shohet
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Merry
authors.initials: M
authors.lastname: Lindsey
authors.forename: Claude Jourdan
authors.initials: CJ
authors.lastname: Le Saux
mesh_terms: D000818:Animals; D015415:Biomarkers; D001835:Body Weight; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D003452:Cryosurgery; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000601:surgery*; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051242:Caveolin 1; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020784:Matrix Metalloproteinase 8