Abstract 13901: Metformin Stimulates Ischemia-Induced Revascularization through an AMPK/eNOS-Dependent Pathway
Background: Type2 diabetes causes increased morbidity of coronary and peripheral artery diseases due to microvascular rarefaction and impaired collateral vessel growth under ischemic conditions. Metformin is a widely used first-line drug for the treatment of type2 diabetes, and reduces cardiovascular events in patients with type2 diabetes. However, little information is available about the functional role of metformin regulating angiogenesis. Here, we investigated whether metformin modulates the revascularization processes in vivo employing a hindlimb model of ischemia-induced angiogenesis.
Methods: Wild-type (WT, n=20) mice or eNOS deficient (eNOS-KO, n=10) mice were randomly divided into two groups. One group received metformin as daily oral administration by gastric tube (300mg/kg/day) and the other didn’t (control group). Mice were subjected to unilateral hindlimb ischemia. Revascularization was determined by laser Doppler analysis and capillary density stained with CD31. The phosphorylation levels of AMPK and eNOS were assessed by Western blot analysis.
Results: There were no significant differences in metabolic parameters such as plasma glucose and insulin levels between metformin group and control group. WT mice treated with metformin showed accelerated limb perfusion on post-operative day 28 based upon laser Doppler measurements of blood flow (metformin group, 0.67±0.12 vs. control group, 0.52±0.21; P<0.05) and increased capillary density in ischemic adductor muscle (metformin group, 2.63±1.40 vs. control group, 0.63±0.74; P<0.01). Treatment with metformin significantly enhanced ischemia-induced increase in AMPK and eNOS phosphorylation levels of muscle tissues in WT mice. In eNOS-KO mice, metformin significantly increased the phosphorylation of AMPK in ischemic tissues, but did not affect blood flow recovery in ischemic limbs after surgery.
Conclusions: Metformin can promote revascularization in response to tissue ischemia via an AMPK/eNOS-dependent mechanism. Our study indicates that, in addition to its glucose-lowering effect, metformin has beneficial effects on the treatment of ischemic peripheral artery diseases including improvement of revascularization.
- © 2012 by American Heart Association, Inc.