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...

Background-Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function. Methods and Results-Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (⌬FDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; PϭNS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (⌬mevalonate-simvastatin, Ϫ1.04Ϯ0.62 versus ⌬mevalonate-ezetimibe, 1.79Ϯ0.94 ng/mL; PϽ0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5Ϯ0.6% versus 5.1Ϯ0.7%; PϽ0.01) but not after ezetimibe treatment (5.6Ϯ0.5% versus 5.8Ϯ0.6%; PϭNS). ⌬FDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by Ͼ100% (PϽ0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect. Conclusions-Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in

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