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

Abstract

Key Words: endothelial progenitor cells Ⅲ nitrates Ⅲ nitric oxide Ⅲ reactive oxygen species Ⅲ atherosclerosis Ⅲ free radicals N itrate compounds have been used in the treatment of myocardial ischemia for more than a hundred years. Their common mechanism is the release of nitric oxide (NO), but the majority of nitrates, such as nitroglycerine (NTG) or isosorbide-5-dinitrate (ISDN), additionally stimulate production of reactive oxygen species (ROS). [1][2][3][4][5] This may counteract the beneficial effects of NO on the endothelium. 6 Indeed, NTG treatment was shown to reduce NO bioavailability 1 as a result of increased superoxide anion (O 2 Ϫ ) and peroxynitrite production. 7,8 Clinically, prolonged NTG therapy leads to the development of endothelial dysfunction and nitrate tolerance. 2,9 Therefore, the use of long-acting nitrates with less development of tolerance has become routine in chronic treatment of cardiac ischemia. However, even long-acting nitrates, such as ISDN, may increase ROS production in endothelial cells, smooth muscle cells, and platelets (reviewed by Schwemmer and Bassenge 10 ). In contrast, treatment with pentaerythritol tetranitrate (PETN) was not associated with increased ROS production in patients. 2 PETN treatment did also not stimulate endothelial ROS formation, and displayed antiatherosclerotic effects. 11-13 Indeed, PETN, but not ISDN, prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. 11,14 Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the blood and contribute to the formation of new blood vessels and homeostasis of the vasculature. 15,16 NO is a major regulator of EPC mobilization, differentiation, and function. [17][18][19][20] Although nitrates are potent NO releasing substances, the effects of long-acting nitrates on circulating levels and function of EPCs have not been determined so far. We therefore compared the effects of ISDN and PETN (or its major metabolite pentaerythrityl trinitrate [PETriN]) on EPC number and function in healthy rats and rats after myocardial infarction. Additional in vitro studies were performed with human EPCs to identify potential underlying events leading to the different effects of both nitrates.

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…For instance, many nitrates are known to induce endothelial dysfunction due to induction of oxidative stress (64,79). An interesting exception seems to be the organic nitrate pentaerythritol tetranitrate (PETN) that does not induce endothelial dysfunction nor increase oxidative stress in animals or humans (97,106).…”

The Peroxisome Proliferator–Activated Receptor-γ Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients With Coronary Artery Disease and Normal Glucose Tolerance

“…The NADPH oxidase is an important source of endothelial superoxide anions (38). Reactive oxygen species impair the function of both mature and immature endothelial cells (16,39,40). Treatment of cultured EPCs from healthy volunteers (n ϭ 4) with pioglitazone (10 mol/l, 24 h) decreased basal NADPH oxidase activity from 40 Ϯ 3.29 to 16 Ϯ 8.34 relative light units (RLU)/g.…”

Angelica sinensispolysaccharides inhibit endothelial progenitor cell senescence through the reduction of oxidative stress and activation of the Akt/hTERT pathway

“…Superoxide anion production in EPCs was assessed by staining with the fluorescent dye dihydroethidium (DHE) as described previously (Thum et al, 2007). DHE displays blue fluorescence in the unoxidized form, whereas it displays red fluorescence when oxidized to 2-hydroxyethidium by the superoxide anion.…”