Research Papers:
Chronic hyperuricemia impairs blood flow recovery in the ischemic hindlimb through suppression of endothelial progenitor cells
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Abstract
I-Chun Chen1, Chin-Sung Kuo1,2, Chih-Cheng Wu3,4,5,6, Hsiao-Ya Tsai1, Chih-Pei Lin7,8, Szu-Yuan Li1,9, Ruey-Hsing Chou1,3,10, Po-Hsun Huang1,3,10, Jaw-Wen Chen3,10,11,12 and Shing-Jong Lin1,3,10,11,13
1Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
2Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
3Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
4National Tsing-Hua University, Institute of Biomedical Engineering, Hsinchu, Taiwan
5National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
6Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Hsinchu, Taiwan
7Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
8Department of Biotechnology and Laboratory Science in Medicine and Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan
9Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
10Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
11Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
12Institute and Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
13Taipei Medical University, Taipei, Taiwan
Correspondence to:
Po-Hsun Huang, email: [email protected]
Chih-Cheng Wu, email: [email protected]
Chin-Sung Kuo, email: [email protected]
Keywords: hyperuricemia; endothelial progenitor cell; ischemia; neovascularization
Received: August 14, 2017 Accepted: January 02, 2018 Published: January 22, 2018
ABSTRACT
Objective: Chronic hyperuricemia is associated with cardiovascular disease, but its impact on endothelial progenitor cells (EPC) and ischemia-induced neovascularization remains unclear. Herein we investigated whether chronic hyperuricemia could impede blood flow recovery in response to tissue ischemia by suppression of EPC.
Methods: Human EPC were isolated and cultured in a high-level uric acid medium for functional testing. Cell proliferation, nitric oxide (NO) production and apoptosis assay were examined. A chronic hyperuricemia mouse model was established by potassium oxonate treatment and/or a high-level uric acid diet to evaluate the actions of chronic hyperuricemia on ischemia-induced blood flow recovery. After 4 weeks of drug treatment, hindlimb ischemia surgery was performed in the control and hyperuricemia mice. Blood flow recovery was followed up every week before and after ischemic surgery using a laser Doppler Perfusion Imager System. The circulating EPC number in the peripheral blood was determined by flow cytometry (Sca-1+/Flk-1+).
Results: Incubation with a high-level uric acid medium (10 mg/dL) significantly suppressed EPC proliferation, reduced NO production, and lessened phosphorylation of Akt and eNOS. Moreover, EPC treated with high-level uric acid increased reactive oxygen species production, promoted cellular apoptosis and senescence, and also inhibited EPC tube formation. Four weeks after hindlimb ischemia surgery, the chronic hyperuricemia mice had significantly reduced tissue reperfusion, EPC mobilization, and impaired neovascularization in the ischemic hindlimbs compared with the control mice.
Conclusions: Chronic hyperuricemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC.
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