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(Circulation. 2007;116:163-173.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

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

Restoration by the Peroxisome Proliferator-Activated Receptor- Agonist Rosiglitazone

Sajoscha A. Sorrentino, MD^*; Ferdinand H. Bahlmann, MD, PhD^*; Christian Besler, BS; Maja Müller, BS; Svenja Schulz, BS; Nina Kirchhoff, BS; Carola Doerries, MD; Tibor Horváth, BS; Anne Limbourg, MD; Florian Limbourg, MD; Danilo Fliser, MD; Hermann Haller, MD; Helmut Drexler, MD; Ulf Landmesser, MD

From Abteilung Kardiologie und Angiologie (S.A.S., C.B., M.M., S.S., N.K., C.D., T.H., A.L., F.L., H.D., U.L.) and Abteilung Nephrologie (F.H.B., D.F., H.H.), Medizinische Hochschule Hannover, Hannover, Germany.

Correspondence to Ulf Landmesser, MD, Hannover Medical School, Department of Cardiology and Angiology, OE6880, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. E-mail Landmesser.Ulf{at}MH-Hannover.de

Received December 15, 2006; accepted May 7, 2007.

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 (n=30) and healthy subjects (n=10) 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: 8±3% versus 37±10%; P<0.001). 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, 8±1% versus 38±5%; P<0.001).

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 proliferator-activated receptor- agonism promotes vascular repair.

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