Abstract 19493: Sirt7 Contributes to Myocardial Tissue Repair by Maintaining TGF-β Signaling Pathway
Background: Sirt7, one of the seven members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process.
Methods and Results: In wild type (WT) mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction (MI) and hindlimb ischemia, particularly at the active wound healing site. Homozygous Sirt7 deficient (Sirt7-/-) mice showed susceptibility to cardiac rupture after MI, delayed blood flow recovery following hindlimb ischemia and impaired wound healing after skin injury, compared to WT mice. Histological analysis showed reduced fibrosis, fibroblast differentiation and inflammatory cell infiltration in the border zone of infarction in Sirt7-/- mice. In vitro, Sirt7-/- mice-derived or Sirt7 siRNA-treated cardiac fibroblasts showed reduced TGF-β signal activation and low expression levels of fibrosis-related genes compared with WT mice-derived or control siRNA-treated cells. These changes were accompanied by reduction in TGF-β receptor I (TβRI) protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. TβRI downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase C, alpha (PICK1) was involved in this process.
Conclusions: Sirt7 maintains TβRI by modulating autophagy and contributes to tissue repair processes.
Author Disclosures: S. Araki: None. Y. Izumiya: None. Y. Kimura: None. S. Hanatani: None. Y. Onoue: None. S. Yamamura: None. T. Braun: None. E. Bober: None. H. Ogawa: Honoraria; Modest; AstraZeneca K.K., Boehringer Ingelheim Japan, Bristol-Myers Squibb Company, Mitsubishi Tanabe Pharma, Pfizer Japan Inc, Sanofi K.K., Teijin Pharma Co., Ltd. Honoraria; Significant; Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.. Other; Modest; Astellas Pharma Inc, Bristol-Myers Squibb Company, Chugai Pharmaceutical Co, Ltd., Dainippon Sumitomo Pharma Co., Ltd., MSD K.K., Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer Japan Inc, Takeda Pharmaceutical Co., Ltd.. Other; Significant; Bayer, Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Sanofi K.K..
- © 2015 by American Heart Association, Inc.