Published Online
on September 24, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Adaptive and Maladptive Effects of Smad3 Signaling in the Adult Heart Following Hemodynamic Pressure Overloading

Vijay Divakaran; Julia Adrogue; Masakuni Ishiyama; Mark L. Entman; Sandra Haudek; Natarajan Sivasubramanian and Douglas L. Mann¹

Baylor College of Medicine, Houston, TX

^* Corresponding author; email: dmann{at}bcm.tmc.edu

Background—Previous studies suggest that transforming growth factor- beta (TGF-β) provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of TGF-β 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 (TAC) in SMAD3 null (SMAD3^-/-) and littermate control mice (age 10-12 weeks). Cumulative survival 20 days post-TAC was significantly less in the SMAD3^-/- mice when compared to littermate controls (43.6% vs 90.9%, p<0.01). TAC 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.

Key Words: hypertrophy • signal transduction • fibrosis • microRNA • pressure overload