RATIONALE: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-beta/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. OBJECTIVE: The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. METHODS AND RESULTS: Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3-/- infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-beta1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3-/- fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-beta-induced expression of alpha-smooth muscle actin. In addition, Smad3-/- fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-beta1-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-beta-induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. CONCLUSIONS: Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.
RATIONALE: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-beta/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. OBJECTIVE: The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. METHODS AND RESULTS:Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3-/- infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-beta1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3-/- fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-beta-induced expression of alpha-smooth muscle actin. In addition, Smad3-/- fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-beta1-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-beta-induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. CONCLUSIONS: Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.
Authors: James J Tomasek; Giulio Gabbiani; Boris Hinz; Christine Chaponnier; Robert A Brown Journal: Nat Rev Mol Cell Biol Date: 2002-05 Impact factor: 94.444
Authors: G S Ashcroft; X Yang; A B Glick; M Weinstein; J L Letterio; D E Mizel; M Anzano; T Greenwell-Wild; S M Wahl; C Deng; A B Roberts Journal: Nat Cell Biol Date: 1999-09 Impact factor: 28.824
Authors: Marcin Bujak; Marcin Dobaczewski; Carlos Gonzalez-Quesada; Ying Xia; Thorsten Leucker; Pawel Zymek; Vikas Veeranna; Andrew M Tager; Andrew D Luster; Nikolaos G Frangogiannis Journal: Circ Res Date: 2009-09-24 Impact factor: 17.367
Authors: Chan Woo Kim; Anastassia Pokutta-Paskaleva; Sandeep Kumar; Lucas H Timmins; Andrew D Morris; Dong-Won Kang; Sidd Dalal; Tatiana Chadid; Katie M Kuo; Julia Raykin; Haiyan Li; Hiromi Yanagisawa; Rudolph L Gleason; Hanjoong Jo; Luke P Brewster Journal: Circulation Date: 2017-08-04 Impact factor: 29.690
Authors: Angela S Pechenino; Li Lin; Fiona N Mbai; Alison R Lee; Xian-Min He; John N Stallone; A A Knowlton Journal: Physiol Genomics Date: 2011-07-12 Impact factor: 3.107
Authors: Craig B Woda; Sarah Bruneau; Anne Linde Mak; Zdenka Haskova; Kaifeng Liu; Chandra C Ghosh; David M Briscoe Journal: Biochem Biophys Res Commun Date: 2019-09-18 Impact factor: 3.575