Abstract 785: Pressure-Overload Induced Cardiac Hypertrophy is Associated with Increased Mortality in SMAD3 Deficient Mice
Myostatin is a secreted factor that belongs to the transforming growth factor-beta superfamily. Myostatin negatively regulates cell growth in skeletal muscle cells through SMAD3-dependent repression of MyoD. Although the effects of myostatin/SMAD3 signaling in the heart are not known, recent studies have shown that myostatin/SMAD3 are upregulated in cardiac myocytes after cardiac injury, raising the possibility that SMAD3 may negatively modulate hypertrophic growth during cardiac injury. The purpose of this study was to determine the role of SMAD3 signaling in the heart following hemodynamic pressure overload in vivo. 10 week old SMAD3 deficient (KO) and wild-type (WT) mice underwent transverse aortic constriction (TAC) or sham operation. Hearts were examined at 20 days, cardiac tissue was processed for morphometric and histological analysis, and Kaplan-Meyer curves were used to determine survival.
Results: There was a significant (p< 0.05) decrease in survival in SMAD3 KO mice (45%) compared to WT (95%) following TAC (see Figure⇓). Heart weight/ body weight ratio was increased in SMAD3 KO compared to WT mice (9.3±0.93 vs. 6.7±0.4 mg/gm, p<0.01), and cardiac myocyte cell cross-sectional area was increased in SMAD3 KO mice vs WT mice at 20 days post TAC (280 ± 6 vs 236 ±5 um, p<0.01). Consistent with the effects of SMAD3 on collagen synthesis, we observed a decrease in collagen in SMAD3 KO vs WT mice at 20 days post TAC (p<0.02).
Conclusion: Taken together these results suggest that SMAD3 plays a critical role in pressure overload cardiac hypertrophy by suppressing excessive cardiac hypertrophy, while allowing for adaptive fibrosis.