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. METHODS AND 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.
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. METHODS AND 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: D Zhang; V Gaussin; G E Taffet; N S Belaguli; M Yamada; R J Schwartz; L H Michael; P A Overbeek; M D Schneider Journal: Nat Med Date: 2000-05 Impact factor: 53.440
Authors: N Sivasubramanian; M L Coker; K M Kurrelmeyer; W R MacLellan; F J DeMayo; F G Spinale; D L Mann Journal: Circulation Date: 2001-08-14 Impact factor: 29.690
Authors: Kathleen C Flanders; Catherine D Sullivan; Makiko Fujii; Anastasia Sowers; Mario A Anzano; Alidad Arabshahi; Christopher Major; Chuxia Deng; Angelo Russo; James B Mitchell; Anita B Roberts Journal: Am J Pathol Date: 2002-03 Impact factor: 4.307
Authors: Thomas Doetschman; Joey V Barnett; Raymond B Runyan; Todd D Camenisch; Ronald L Heimark; Henk L Granzier; Simon J Conway; Mohamad Azhar Journal: Cell Tissue Res Date: 2011-09-28 Impact factor: 5.249
Authors: Navin K Kapur; Szuhuei Wilson; Adil A Yunis; Xiaoying Qiao; Emily Mackey; Vikram Paruchuri; Corey Baker; Mark J Aronovitz; S Ananth Karumanchi; Michelle Letarte; David A Kass; Michael E Mendelsohn; Richard H Karas Journal: Circulation Date: 2012-05-16 Impact factor: 29.690
Authors: Raul R Blanco; Harland Austin; Richard N Vest; Ravinder Valadri; Wei Li; Bernard Lassegue; Qing Song; Barry London; Samuel C Dudley; Heather L Bloom; Charles D Searles; A Maziar Zafari Journal: J Card Fail Date: 2012-08-09 Impact factor: 5.712
Authors: Gina M Warner; Jingfei Cheng; Bruce E Knudsen; Catherine E Gray; Ansgar Deibel; Justin E Juskewitch; Lilach O Lerman; Stephen C Textor; Karl A Nath; Joseph P Grande Journal: Am J Physiol Renal Physiol Date: 2012-02-29