Abstract 11200: Sirt7 is Essential for Proper Wound Healing Processes after Mouse Model of Myocardial Infarction by Inhibiting smad7-mediated TGF-β Receptor I Degradation
Introduction: Sirt7, one of the seven members of the mammalian sirtuin family, is recently reported to modulate oncogenic transformation. To date, functional role and molecular target of Sirt7 remains unclear in the heart. Hypothesis: Sirt7 contributes to proper wound healing processes after myocardial infarction (MI) by modulating cardiac fibroblast function.
Methods: MI was created in Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Sirt7 knockdown experiments by using siRNA were performed with rat neonatal cardiac fibroblast.
Results: Sirt7 expression was increased at 1 day after MI in Border Zone (BZ) of myocardium and this change was more apparent at 3 days after MI in WT mice. Echocardiographic and hemodynamic parameters were not different between WT and Sirt7-/- mice 3 days after MI. However, Sirt7-/- mice were susceptibility to cardiac rupture within 1 week after MI (Sirt7-/- mice 63.2% vs. WT mice 19.2%, p<0.01). Histological analysis revealed that interstitial fibrosis and α-SMA positive myofibroblast in the BZ was decreased in Sirt7-/- mice. These changes were accompanied by the reduction in collagen I and α-SMA gene expression. In cardiac fibroblast, knockdown of Sirt7 inhibited basal and TGFβ1-induced fibroblast proliferation both in 24 or 48 hours after siRNA transfection. Gel contraction assay showed that the contractile ability of collagen network in response to TGFβ stimulation was significantly decreased by Sirt7 knockdown compared with control siRNA. TGFβ1-induced differentiation from fibroblast to myofibroblast, assessed by MTS assay, was attenuated by Sirt7 siRNA. TGF-β1 stimulation dramatically increased phosphorylation of smad2 and ERK, but pretreatment with sirt7 siRNA abolished these changes in 2 to 4 hours after TGF-β1 treatment. Mechanistically, knockdown of Sirt7 accelerated TGFβ receptor I (TβRI) degradation upon TGF-β1 stimulation in time dependent manner. The effects of Sirt7 knockdown on TβRI degradation were rescued by Smad7 knockdown.
Conclusions: Sirt7 contributes to TβRI stabilization via smad7-dependent manner. Sirt7 is essential for proper wound healing following after MI by modulating TβRI degradation.
- © 2012 by American Heart Association, Inc.