Oxidant Stress Impairs In Vivo Reendothelialization Capacity of Endothelial Progenitor Cells From Patients With Type 2 Diabetes Mellitus

Abstract

Background-Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury.We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-␥ agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals. Methods and Results-In vivo reendothelialization capacity of EPCs from diabetic patients (nϭ30) and healthy subjects (nϭ10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID PO) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8Ϯ3% versus 37Ϯ10%; PϽ0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47 phox reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8Ϯ1% versus 38Ϯ5%; PϽ0.001). Conclusions-In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase-dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferatoractivated receptor-␥ agonism promotes vascular repair. association of reduced EPC numbers with peripheral artery disease and its severity in diabetic patients. 6,7 Experimental studies have demonstrated that EPCs promote endothelial repair after injury. 8 -10 In diabetic patients, however, an impaired migration capacity and tube formation of EPCs have been observed in vitro, 11,12 and a diabetesinduced delay in reendothelialization by EPCs has been described for diabetic mice, 13 raising the question of whether the in vivo reendothelialization capacity of human EPCs from patients with diabetes mellitus is altered. Moreover, mechanisms underlying EPC dysfunction in diabetic individuals remain largely unknown. In the present study, we therefore compared the in vivo reendothelialization capacity of EPCs derived from diabetic and healthy subjects and analyzed mechanisms of EPC dysfunction.Increased oxidant s...

High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment

“…25) Inhibition of oxidative stress has reversed diabetic EPC dysfunction, suggesting that increased ROS plays key roles in diabetic vascular impairment. 5,25,26) The increased level of ROS in EPCs was also detected under HG condition, 27) and here we further demonstrated the enhanced mitochondrial ROS and disruption of mitochondrial membrane potential in HG-exposed EPCs, suggesting its role in HG-induced autophagy in EPCs. Mitochondrial ROS generation and subsequent mitochondrial oxidative damage may modulate mitophagy, a form of micro-autophagy, potentially contributing to autophagic cell death.…”

Pioglitazone Inhibits Angiotensin II–Induced Senescence of Endothelial Progenitor Cell

“…In the future, it will be necessary to establish a standard method for the culture of EPC. In recent studies, EPCs have generally benn defined by DiLDL/lectin double-positive cells (30,31). The molecular and phenotypic determinants of EPCs and their precursors remain largely unknown.…”

A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications

“…This debate aside, one might even question what an endothelial cell is. If we use a minimalist definition of the endothelium as the internal lining of blood vessels, early/ myeloid EPCs have repeatedly been shown to contribute to the restoration of endothelial integrity [8,25], although this occurs transiently and without full differentiation and integration with the resident endothelium [26].…”

“…Traditionally, neoangiogenesis after ischaemia and reendothelisation after endothelial injury were considered to be accomplished through the activation, proliferation and migration of resident endothelial cells. However, following the discovery of endothelial progenitor cells (EPCs), defective re-endothelisation and neoangiogenesis in diabetes have been attributed to circulating EPCs with an impaired regenerative capacity [4,8], thereby placing circulating cells at the centre of a new pathophysiological model of diabetic vascular disease [9,10]. Interest around these cells has been further amplified by the possibility of developing cell-based therapies for vascular complications [11,12].…”