Abstract 11965: Sirt7 Regulates Wound Healing by Modulating TGFβ Signaling
Introduction: Sirtuins are NAD-dependent deacetylases and seven different homologues exist in mammals. Sirt7 is the least investigated Sirtuins. To date, functional role and molecular target of Sirt7 remains unclear in wound healing processes.
Hypothesis: Sirt7 contributes to proper wound healing processes after myocardial infarction (MI) and dermal injury by modulating fibroblast function.
Methods: MI and dermal injury were 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 and 3, 14 days after MI in Border Zone (BZ) of myocardium. 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% v.s. 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. Dermal injury repairs also delayed in Sirt7 KO mice compared with WT mice. In cardiac fibroblast, knockdown of Sirt7 inhibited basal and TGFβ1-induced fibroblast proliferation both in 24 or 48 hours after siRNA transfection. Collagen 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 α-SMA and SM-22 expression, was attenuated by Sirt7 siRNA. We also found that knockdown of Sirt7 decreased TGFβ receptor I (TβRI) expression. We investigated whether Sirt7 modulated any factors that regulate TβRI expression. Finally we found that Sirt7 regulated PICK1 expression and knockdown of PICK1 abolished the effect of Sirt7 siRNA.
CONCLUSIONS: Sirt7 contributes to TβRI expression via PICK1-dependent manner. Sirt7 is essential for proper wound healing following after MI and dermal injury by modulating TβRI expression.
- © 2013 by American Heart Association, Inc.