Endothelium-Selective Activation of AMP-Activated Protein Kinase Prevents Diabetes Mellitus-Induced Impairment in Vascular Function and Reendothelialization via Induction of Heme Oxygenase-1 in Mice

Article

关键词: IMPROVES INSULIN SENSITIVITY;    NITRIC-OXIDE SYNTHASE;    PROGENITOR CELLS;    IN-VIVO;    OXIDATIVE STRESS;    ARTERIAL INJURY;    CARBON-MONOXIDE;    PROMOTES;    NEOVASCULARIZATION;    ANGIOGENESIS;   

DOI  :  10.1161/CIRCULATIONAHA.112.108159

来源: SCIE

【 摘 要 】

Background-Endothelial damage and dysfunction are crucial mediators that link diabetes mellitus with atherosclerotic cardiovascular disease. AMP-activated kinase (AMPK) has been implicated in regulation of both energy metabolism and vascular homeostasis. The present study investigated whether endothelium-selective activation of AMPK prevents diabetes mellitus-induced endothelial damage and vascular dysfunction by improving reendothelialization 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 reendothelialization 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. Compared with wild-type littermates, the CA-AMPK transgenic mice were resistant to diabetes mellitus-induced impairment in endothelium-dependent relaxation and reendothelialization 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)-1 alpha were upregulated in EPCs derived from the transgenic mice, whereas AMPK-mediated elevation of serum SDF-1 alpha levels and improvements of EPC function and reendothelialization were all abrogated by pharmacological inhibition of heme oxygenase-1. Conclusions-Endothelium-specific AMPK activation is sufficient to protect against diabetes mellitus-induced aggravation of vascular injury by promoting EPC function and reendothelialization via upregulation of heme oxygenase-1 and SDF-1 alpha. (Circulation. 2012;126:1267-1277.)

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