Abstract 873: Differential Effects of Long-Acting Nitrates on Endothelial Progenitor Cells are Determined by Reactive Oxygen Species Formation
Reduced levels and impaired function of endothelial progenitor cells (EPC) contribute to the development of coronary artery disease. Endothelial nitric oxide synthase derived NO regulates in part mobilisation and differentiation of progenitor cells. Nitrate compounds release NO and may favourably affect number and function of EPC. We compared the effects of different nitrates on EPC function in vitro and on circulating EPC levels in vivo. Inhibition of endogenous NO production by N-nitro-l-arginine led to an impaired differentiation and function of EPC in vitro. Surprisingly, treatment of EPC with isosorbide dinitrate (ISDN; 100μM) likewise reduced migration of EPC by 20.7±3.1%, whereas pentaerythritol-trinitrate (PETriN; 100μM), the active metabolite of pentaerythritol-tetranitrate (PETN), improved migratory capacity of EPC by 26.6%±6.9% (p<0.05). Concomitant treatment of EPC with PETriN and a NO-scavenger, abolished the beneficial effect of PETriN. Incorporation of EPC into vascular structures on matrigel was not changed upon treatment with PETriN, but significantly reduced by 42.3±4.2% (p<0.05) after treatment with ISDN. ISDN, but not PETriN, significantly increased reactive oxygen species (ROS) in cultured EPC (fluorescence microscopic detection). Addition of pegylated superoxide-dismutase normalized ISDN-induced ROS production and migratory capacity of EPC. In vivo, release of PETriN or ISDN for 3 days from implanted osmotic mini-pumps increased circulating EPC levels about 2-fold. Ex vivo experiments demonstrated improved function of EPC only after treatment with PETriN, whereas EPC from ISDN treated animals had dysfunctional EPC with increased intracellular ROS formation. Long-acting nitrates increase levels of circulating EPC. However, ISDN increased ROS formation and impaired EPC function, whereas PETriN had favourable effects on EPC.