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Arteriosclerosis, Thrombosis, and Vascular Biology
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on January 25, 2007

Arteriosclerosis, Thrombosis, and Vascular Biology. 2007
Published online before print January 25, 2007, doi: 10.1161/01.ATV.0000258787.18982.73
A more recent version of this article appeared on April 1, 2007
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Submitted on October 16, 2006
Accepted on December 29, 2006

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 ; and 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.

* To whom correspondence should be addressed. 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.
Key words: endothelial progenitor cells • nitrates • nitric oxide • reactive oxygen species • atherosclerosis • free radicals




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