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Original Articles

Adaptive and Maladptive Effects of SMAD3 Signaling in the Adult Heart After Hemodynamic Pressure Overloading

Vijay Divakaran, MD; Julia Adrogue, MD; Masakuni Ishiyama, MD; Mark L. Entman, MD; Sandra Haudek, PhD; Natarajan Sivasubramanian, PhD and Douglas L. Mann, MD

From the Sections of Cardiology (V.D., J.A., M.I., N.S., D.L.M.) and Cardiovascular Sciences (M.L.E., S.H.), and Departments of Medicine and Molecular Physiology and Biophysics (D.L.M.), Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Tex.

Correspondence to Douglas L. Mann, MD, 1709 Dryden Rd, BCM620, F.C. 9.30, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu

Received September 19, 2008; accepted August 27, 2009.

Background— Previous studies suggest that transforming growth factor-β provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of transforming growth factor-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 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.

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

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