Abstract 12126: Sirt7 Regulates Tgfb Signaling by Modulating Autophagy
Introduction: Sirt7 is a NAD-dependent histon deacetylase. Recent study shows Sirt7 modulates cancer progression by modulating oncogenic gene expression. However, the role of Sirt7 remains unclear in wound healing processes.
Hypothesis: Sirt7 contributes to proper wound healing processes after myocardial infarction (MI) by modulating fibrosis.
Methods: MI 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 mRNA expression was increased at 1, 3 and 14 days after MI in the myocardium of border zone (BZ). Histological analysis revealed that Sirt7 protein increased in the fibrosis area of BZ at 3 days after MI. Sirt7-/- mice were susceptibility to cardiac rupture within 1 week after MI despite no change of cardiac function between WT and Sirt7-/- mice. Interstitial fibrosis and α-SMA positive myofibroblast in BZ was decreased in Sirt7-/- mice at 3 days after MI. In cardiac fibroblast, TGFβ1-induced differentiation from fibroblast to myofibroblast, assessed by α-SMA, was attenuated by Sirt7 siRNA. Recent study shows Sirt7 modulates autophagy induction by interacting with mTOR. It is also reported that autophagy reduces TGFβ1-induced fibrosis. Knockdown of Sirt7 increased LC3-II and decreased p62. These data suggested that knockdown of Sirt7 increased autophagic activity. We also found that knockdown of Sirt7 decreased TGFβ receptor I (TβRI) protein expression and its downstream signaling. Conversely, autophagy inhibitor, such as chloroquine, attenuated TGFβ1-induced TβRI degradation.
Conclusions: Autophagy regulates TGFβ1-induced TβRI degradation. Knockdown of Sirt7 accelerates TβRI degradation by increasing autophagy. Sirt7 is essential for proper wound healing following after MI by modulating TβRI degradation.
Author Disclosures: S. Araki: None. Y. Izumiya: None. S. Hanatani: None. Y. Kimura: None. Y. Onoue: None. T. Braun: None. E. Bober: None. H. Ogawa: Other Research Support; Modest; AstraZeneca, Astellas, Boehringer lngelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo Pharma, Kowa, MSD, Novartis, Pfizer, Sanofi, Takeda. Other Research Support; Significant; Bayer, Chugai, Otsuka. Honoraria; Modest; AstraZeneca, Bayer, Pfizer, Sanofi, Takeda. Honoraria; Significant; Daiichi Sankyo, MSD.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.