Abstract 11244: Sirt7 Promotes Blood Flow Recovery in Response to Ischemia by Modulating Endothelial Functions and Adhesion Molecule Expression
Introduction: Sirt7 is a mammalian sirtuin which is known to promote tumor progression by deacetylating H3K18. Tumor growth required angiogenic responses, however, little is known about the role of Sirt7 in these processes.
Hypothesis: Sirt7 promotes angiogenesis in response to tissue ischemia.
Methods: Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice were subjected to unilateral femoral artery ligation to induce hindlimb ischemia. To achieve bone marrow (BM) transfer, recipient WT mice were irradiated at 9 Gy and then intravenously received BM cells from WT or Sirt7 -/- mouse. Loss- and gain-of-function experiments were performed with human umbilical vein endothelial cells (HUVECs).
Results: Blood flow recovery of hindlimb following ischemic surgery was significantly impaired in Sirt7-/- mice compared with WT mice. Immunostaining of ischemic gastrocnemius muscle showed that a significant decrease in capillary density and inflammatory cell infiltration in Sirt7-/- mice compared with WT mice. Angiogenesis-related transcript expression were decreased in ischemic adductor muscle tissue in Sirt7-/- compared with WT mice. Gene expression of inflammation-related genes, such as IL-1β, IL-6, TNF-α, and MCP-1 were also significantly lower in Sirt7-/- than in WT mice. There was no difference in blood flow recovery following ischemic surgery between WT mice transplanted with WT or Sirt7-/- BM cells, suggesting that Sirt7 deficiency in BM cells have little effect on blood flow recovery in response to hindlimb ischemia. In vitro, knockdown of endogenous Sirt7 by siRNA attenuated tube formation, proliferation and migration. Conversely, overexpression of Sirt7 by adenovirus increased tube formation and proliferation. Mechanistically, knockdown of endogenous Sirt7 significantly decreased VCAM-1 but not ICAM-1 mRNA and protein expression. In addition, anti-angiogenic growth factor semaphorin3A expression was upregulated by knockdown of Sirt7. Impaired cell proliferation by Sirt7 knockdown was restored by knockdown of semapphorin3A.
Conclusions: Sirt7 regulates angiogenesis by modulating endothelial function and adhesion molecule expression. Sirt7 plays a key role in ischemia-induced angiogenic response in mice.
- © 2013 by American Heart Association, Inc.