Endothelium-Selective Activation of AMP-Activated Protein Kinase Prevents Diabetes-Induced Impairment in Vascular Function and Re-Endothelialization via Induction of Heme Oxygenase-1 in Mice
Background—Endothelial damage and dysfunction are crucial mediators that link diabetes with atherosclerotic cardiovascular disease. AMP-activated kinase (AMPK) has been implicated in regulating both energy metabolism and vascular homeostasis. The present study investigated whether endothelium-selective activation of AMPK prevents diabetes-induced endothelial damage and vascular dysfunction by improving re-endothelialization in mice.
Methods and Results—Transgenic mice with endothelium-selective expression of a constitutively-active (CA-) AMPK were generated and rendered diabetic by the injection of streptozotocin. Relaxation and re-endothelialization of carotid arteries and circulating numbers of endothelial progenitor cells (EPCs) were examined after wire-induced denudation. Bone marrow-derived EPCs were isolated to monitor their in vivo and in vitro function. In comparison to wild-type (WT) littermates, the CA-AMPK transgenic mice were resistant to diabetes-induced impairment in endothelium-dependent relaxation and re-endothelialization of their injured carotid arteries. These changes in the transgenic mice were accompanied by increased mobilization of EPCs and enhanced incorporation of EPCs into injured blood vessels. Furthermore, EPCs from the transgenic mice exhibited augmented adhesion, migration and tube formation capacities. At the molecular level, the expression of heme oxygenase (HO)-1 and the secretion of stromal cell-derived factor (SDF)-1α were up-regulated in EPCs derived from the transgenic mice, whereas AMPK-mediated elevation of serum SDF-1α levels and improvements of EPCs function and re-endothelialization were all abrogated by pharmacological inhibition of HO-1.
Conclusions—Endothelium-specific AMPK activation is sufficient to protect against diabetes-induced aggravation of vascular injury by promoting EPC function and re-endothelialization via up-regulation of HO-1 and SDF-1α.
- diabetes mellitus
- endothelial progenitor cells
- vascular function
- AMP-activated kinase
- Received March 26, 2012.
- Accepted July 20, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited