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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:748.)
© 2007 American Heart Association, Inc.

Vascular Biology

Differential Effects of Organic Nitrates on Endothelial Progenitor Cells Are Determined by Oxidative Stress

Thomas Thum; Daniela Fraccarollo; Sabrina Thum; Maximilian Schultheiss; Andreas Daiber; Philip Wenzel; Thomas Munzel; Georg Ertl; Johann Bauersachs

From the Department of Cardiology (T.T., D.F., S.T., M.S., G.E., J.B.), University of Würzburg, University Hospital; the Interdisciplinary Center for Clinical Research (T.T.), Junior Research Group Cardiac Wounding and Healing, University of Würzburg; and Johannes Gutenberg-Universität (A.D., P.W., T.M.), Medizinische Klinik und Poliklinik II, Labor für Molekulare Kardiologie, Mainz, Germany.

Correspondence to Dr Thomas Thum, Medizinische Klinik I, Universitätsklinikum, Julius-Maximilians-Universität, Josef-Schneider-Str. 2, D-97080, Würzburg, Germany. E-mail Thum_T{at}klinik.uni-wuerzburg.de

Objective— Reduced levels and impaired function of endothelial progenitor cells (EPCs) foster development and progression of atherosclerotic lesions. Endothelial nitric oxide synthase (eNOS)–derived NO regulates EPC mobilization and function. Organic nitrates release NO, and therefore may favorably affect EPC biology.

Methods and Results— We compared the effects of 2 different nitrates on circulating EPC numbers and function. Treatment of rats with pentaerythritol-trinitrate (PETriN) or isosorbide dinitrate (ISDN) increased circulating EPC levels. EPC from ISDN- but not PETriN-treated animals displayed impaired migratory capacity and increased reactive oxygen species formation in EPCs. In vitro treatment with ISDN reduced migration and incorporation of human EPCs into vascular structures on matrigel, whereas PETriN improved EPC function. ISDN, but not PETriN, increased NADPH oxidase–mediated oxidative stress in cultured human EPCs. Addition of polyethylene-glycolated superoxide dismutase or diphenyliodonium normalized both ISDN-induced superoxide anion production and impaired migratory capacity of EPCs.

Conclusions— Long-acting nitrates increase levels of circulating EPCs, but differ in their effects on EPC function dependent on the induction of intracellular oxidative stress. Organic nitrates that improve EPC function may confer long-term cardiovascular protection based on their beneficial effects on EPC biology.

Endothelial progenitor cells play a fundamental role in vascular repair and are regulated by nitric oxide. Organic nitrates increased circulating EPC levels but varied in their effects on EPC function. Nitrates that do not increase oxidative stress in EPCs improved cellular function and may confer long-term cardiovascular protection.

Key Words: endothelial progenitor cells • nitrates • nitric oxide • reactive oxygen species • atherosclerosis • free radicals

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