Activation of endothelial NO synthase by a xanthine derivative ameliorates hypoxia-induced apoptosis in endothelial progenitor cells

Abstract

Abstract Objectives Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis, thrombosis and hypertension. Endothelial progenitor cells (EPCs) are primitive bone marrow (BM) cells that possess the capacity to mature into endothelial cells and play a role in neovascularization and vascular remodelling. This study aimed to investigate whether KMUP-1, a synthetic xanthine-based derivative, atorvastatin and simvastatin, can prevent endothelial dysfunction and apoptosis induced by hypoxia and to elucidate the underlying mechanisms. Methods Mononuclear cells were separated and were induced to differentiate into EPCs. KMUP-1, atorvastatin or simvastatin were administered prior to hypoxia. Key findings We found that EPCs exposed to hypoxia increased apoptosis as well as diminished proliferation. Pretreatment with KMUP-1, atorvastatin and simvastatin significantly prevented hypoxia-induced EPCs death and apoptosis, with associated increased of the Bcl-2/Bax ratio, and reduced caspase-3 and caspase-9 expression. We also assessed the nitrite production and Ser(1177)-phospho-eNOS expression and found that KMUP-1, atorvastatin and simvastatin not only increased the secretion of NO compared with the hypoxia group but also upregulated the eNOS activation. Conclusions KMUP-1 inhibited hypoxia-induced dysfunction and apoptosis in EPCs, which may be mediated through suppressing oxidative stress, upregulating eNOS and downregulating the caspase-3 signalling pathway.