Diabetes Impairs the Vascular Recruitment of Normal Stem Cells by Oxidant Damage, Reversed by Increases in pAMPK, Heme Oxygenase-1, and Adiponectin

Abstract

BackgroundAtherosclerosis progression is accelerated in diabetes mellitus (DM) by either direct endothelial damage or reduced availability and function of endothelial progenitor cells (EPCs). Both alterations are related to increased oxidant damage.AimWe examined if DM specifically impairs vascular signaling, thereby reducing the recruitment of normal EPCs, and if increases in antioxidant levels by induction of heme oxygenase-1 (HO-1) can reverse this condition.MethodsControl and diabetic rats were treated with the HO-1 inducer cobalt protoporphyrin (CoPP) once a week for 3 weeks. Eight weeks after the development of diabetes, EPCs harvested from the aorta of syngenic inbred normal rats and labeled with technetium-99m-exametazime were infused via the femoral vein to estimate their blood clearance and aortic recruitment. Circulating endothelial cells (CECs) and the aortic expression of thrombomodulin (TM), CD31, and endothelial nitric oxide synthase (eNOS) were used to measure endothelial damage.ResultsDM reduced blood clearance and aortic recruitment of EPCs. Both parameters were returned to control levels by CoPP treatment without affecting EPC kinetics in normal animals. These abnormalities of EPCs in DM were paralleled by reduced serum adiponectin levels, increased numbers of CECs, reduced endothelial expression of phosphorylated eNOS, and reduced levels of TM, CD31, and phosphorylated AMP-activated protein kinase (pAMPK). CoPP treatment restored all of these parameters to normal levels.ConclusionType II DM and its related oxidant damage hamper the interaction between the vascular wall and normal EPCs by mechanisms that are, at least partially, reversed by the induction of HO-1 gene expression, adiponectin, and pAMPK levels.

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

“…35 In both mature endothelial cells and EPCs, AMPK activation by its agonists suppresses high-glucose-induced reactive oxygen species generation by promoting mitochondrial biogenesis, 17 inhibiting NADPH oxidase activity, 36 and inducing the expression of both mitochondrial uncoupling protein 2 37 and manganese superoxide dismutase. 21 Likewise, the present study shows that the improved EPC function in diabetic CA-AMPK transgenic mice is accompanied by a reduction in intracellular reactive oxygen species levels, which suggests that the suppression of oxidative stress represents an important mechanism accounting for the protective effects of AMPK against diabetes mellitus-induced dysfunction of EPCs.…”

ApoA1

“…[45][46][47][48][49] The decrease in HO-1 expression as a result of increased glucose levels, increases ROS, endothelial cell death, endothelial progenitor function and insulin resistance. 48,[50][51][52] Increased ROS levels and decreased levels of serum adiponectin thereby contribute to the pathogenesis of insulin resistance. 18,53 Humans and rodents deficient in either HO-1 or HO-2 develop vascular dysfunction and die prematurely.…”

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…Treatment of glucose-stressed EPCs with superoxide dismutase in vitro attenuated superoxide anion (O 2 -) generation, restored NO production, and partially normalized their ability to form colonies (35). Treatment of diabetic mice with the HO-1 inducer and thus reducer of oxidative stress cobalt protoporphyrin could in part restore EPC function (72).…”