Differential effects of organic nitrates on endothelial progenitor cells are determined by oxidative stress.
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.


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.
Thum
Thomas
T
Department of Cardiology, University of Würzburg, University Hospital, Würzburg, Germany. Thum_T@klinik.uni-wuerzburg.de
Fraccarollo
Daniela
D
Thum
Sabrina
S
Schultheiss
Maximilian
M
Daiber
Andreas
A
Wenzel
Philip
P
Munzel
Thomas
T
Ertl
Georg
G
Bauersachs
Johann
J
D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D009249:NADP / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010417:Pentaerythritol Tetranitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D010417:Pentaerythritol Tetranitrate; D013481:Superoxides; C100210:pentrinitrol; D009249:NADP; D007548:Isosorbide Dinitrate