title: Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading.
abstract: BACKGROUND
  Previous studies suggest that transforming growth factor-beta provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of transforming growth factor-beta signaling are conveyed through SMAD-dependent or SMAD-independent signaling pathways.
  
  
  RESULTS
  To determine the contribution of SMAD-dependent signaling to cardiac remodeling, we performed transaortic constriction in SMAD3 null (SMAD3(-/-)) and littermate control mice (age, 10 to 12 weeks). Cumulative survival 20 days after transaortic constriction was significantly less in the SMAD3(-/-) mice when compared with littermate controls (43.6% versus 90.9%, P<0.01). Transaortic constriction resulted in a significant increase in cardiac hypertrophy in the SMAD3(-/-) mice, denoted by an increase in the heart weight to tibial length ratio and increased myocyte cross-sectional area. Loss of SMAD3 signaling also resulted in a significant 60% decrease in myocardial fibrosis (P<0.05). A microRNA microarray showed that 55 microRNAs were differentially expressed in littermate and SMAD3(-/-) mice and that 10 of these microRNAs were predicted to bind to genes that regulate the extracellular matrix. Of these 10 candidate microRNAs, both miR-25 and miR-29a were sufficient to decrease collagen gene expression when transfected into isolated cardiac fibroblasts in vitro.
  
  
  CONCLUSIONS
  The results suggest that SMAD3 signaling plays dual roles in the heart: one beneficial role by delimiting hypertrophic growth and the other deleterious by modulating myocardial fibrosis, possibly through a pathway that entails accumulation of microRNAs that decrease collagen gene expression.
authors.affiliation: Sections of Cardiology and Cardiovascular Sciences, and Departments of Medicine and Molecular Physiology and Biophysics, Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Tex, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Divakaran
authors.forename: Julia
authors.initials: J
authors.lastname: Adrogue
authors.forename: Masakuni
authors.initials: M
authors.lastname: Ishiyama
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Sandra
authors.initials: S
authors.lastname: Haudek
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001011:Aorta / Q000601:surgery; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D003250:Constriction; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D006439:Hemodynamics; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D035683:MicroRNAs; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D003094:Collagen