Abstract 12202: Sirt7 Deficiency Impaires Angiogenic Responses in a Mouse Model of Vascular Insufficiency
Introduction: Sirt7, one of the seven members of the mammalian sirtuin family, is involved in the regulation of ribosomal gene transcription. To date, little information is available on the role of SIRT7 in endothelial and vascular homeostasis.
Hypothesis: Sirt7 modulates endothelial function and blood vessel growth in ischemic skeletal muscle.
Methods: The role of SIRT7 in ischemia-induced vessel formation was assessed in a murine model of hind limb ischemia using 10-week-old male homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Hind limb blood flow was measured on postoperative days 0, 7, 14 and 28 using a laser doppler blood flow analyzer and capillary density was assessed by CD31 staining. Sirt7 knockdown experiments were performed with human umbilical vein endothelial cells (HUVECs).
Results: Sirt7 transcripts expression was easily detectable in total RNA isolated from HUVECs. Knockdown of endogenous Sirt7 by small interfering RNA significantly attenuated endothelial differentiation into network structures in response to VEGF stimulation. In vivo, revascularization of hind limb following ischemic surgery was significantly impaired in SIRT7-/- mice compared with the WT mice at 7, 14 and 28 days after surgery. Sections of ischemic gastrocnemius muscle stained with anti-CD31 antibody revealed a significant decrease in capillary density in Sirt7-/- mice compared with WT mice at 7 days after surgery, suggesting that revascularization was impaired at the microcirculatory level. Sirt7 deficiency was associated with an increased incidence of foot and toe necrosis in response to tissue ischemia. Quantitative real-time PCR analysis showed significant decreased in gene expression involved in vascular endothelial homeostasis and remodeling such as HIF-1α, VEGF, FGF2, PDGF-B in adductor muscle tissue in sirt7-/- mice compared with WT mice at 7days after surgery. Moreover, gene expression of inflammation-related genes, such as interleukin-6 and F4/80 were significantly lower in Sirt7-/- mice than in WT mice.
Conclusions: Sirt7 maintains vascular homeostasis by modulating endothelial function and angiogenic growth factors expression. Sirt7 plays a pivotal role in ischemia-induced angiogenic response in mice.
- © 2011 by American Heart Association, Inc.