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Published on: November 2, 2020
Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway
Satoshi Araki1, Yasuhiro Izumiya2, Taku Rokutanda1
1From Departments of Cardiovascular Medicine (S.A., Y.I., T.R., S.H., Y.K., Y.O., H.O.) and Medical Biochemistry (T.S., T.Y., K.Y.), Graduate School of Medical Sciences, Kumamoto University, Japan; Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (A.I., T.B., E.B.); Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Japan (O.Y.); and Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan (N.K., M.K.).
Background:
Sirt7, 1 of the 7 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 mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7(-/-)) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7(-/-) mice. In vitro, Sirt7(-/-) mouse-derived or Sirt7 siRNA-treated cardiac fibroblasts showed reduced transforming growth factor-β signal activation and low expression levels of fibrosis-related genes compared with wild-type mice-derived or control siRNA-treated cells. These changes were accompanied by reduction in transforming growth factor receptor I protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. Transforming growth factor-β receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-Cα was involved in this process.
Conclusion:
Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.
Insights
Sirtuin 7 (Sirt7) is crucial for cardiovascular tissue repair. Loss of Sirt7 impairs wound healing and increases cardiac rupture risk by affecting fibrosis and autophagy.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Tissue Repair Mechanisms
Background:
- Sirtuin 7 (Sirt7) is a member of the mammalian sirtuin family and promotes oncogenic transformation.
- Tumor growth and metastasis involve fibrotic and angiogenic responses.
- The role of Sirt7 in cardiovascular tissue repair remains to be elucidated.
Purpose of the Study:
- To investigate the role of Sirtuin 7 (Sirt7) in the cardiovascular tissue repair process.
- To understand the molecular mechanisms underlying Sirt7's function in tissue regeneration.
Main Methods:
- Utilized wild-type and Sirtuin 7-deficient (Sirt7(-/-)) mice subjected to cardiovascular injury models (myocardial infarction, hind-limb ischemia).
- Performed histological analysis of injured tissues to assess fibrosis, fibroblast differentiation, and inflammation.
- Conducted in vitro studies using cardiac fibroblasts treated with Sirt7 siRNA or from Sirt7(-/-) mice.
- Investigated the role of autophagy and transforming growth factor-β (TGF-β) signaling pathways.
Main Results:
- Sirt7 expression was upregulated in response to cardiovascular injury at wound healing sites.
- Sirt7(-/-) mice exhibited increased cardiac rupture susceptibility, delayed blood flow recovery, and impaired skin wound healing.
- Sirt7 deficiency led to reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration.
- In vitro, loss of Sirt7 reduced TGF-β signaling activation and fibrosis-related gene expression, accompanied by decreased TGF-β receptor I levels.
- Loss of Sirt7 activated autophagy in cardiac fibroblasts, and inhibiting autophagy restored TGF-β receptor I levels.
Conclusions:
- Sirtuin 7 (Sirt7) plays a critical role in cardiovascular tissue repair.
- Sirt7 maintains transforming growth factor receptor I levels by modulating autophagy.
- Dysregulation of Sirt7 impacts fibrosis, inflammation, and overall tissue regeneration capacity.
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