Jiunn-Ren Wu1,2, Jong-Hau Hsu1,2,3, Zen-Kong Dai1,2,3, Bin-Nan Wu3,4, Ing-Jun Chen4, Shu-Fen Liou5, Jwu-Lai Yeh3,4,6. 1. Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 2. Department of Paediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 3. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4. Department and Graduate Institute of Pharmacology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 5. Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan. 6. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
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.
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.
Authors: Moritz Kolster; Mathias Wilhelmi; Claudia Schrimpf; Andres Hilfiker; Axel Haverich; Thomas Aper Journal: J Tissue Eng Date: 2017-03-15 Impact factor: 7.813