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


RESULTS
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.
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Paediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jiunn-Ren
JR
Wu
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Paediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jong-Hau
JH
Hsu
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Paediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Zen-Kong
ZK
Dai
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department and Graduate Institute of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Bin-Nan
BN
Wu
Department and Graduate Institute of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Ing-Jun
IJ
Chen
Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
Shu-Fen
SF
Liou
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department and Graduate Institute of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
Jwu-Lai
JL
Yeh
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000069059:Atorvastatin / Q000494:pharmacology; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D020536:Enzyme Activators; D009573:Nitrites; D010880:Piperidines; D014970:Xanthines; C439304:KMUP 1; D009569:Nitric Oxide; D000069059:Atorvastatin; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
apoptosis; endothelial nitric oxide synthase; endothelial progenitor cells; hypoxia