Chronic hyperuricemia impairs blood flow recovery in the ischemic hindlimb through suppression of endothelial progenitor cells.

I-Chun Chen,Shing-Jong Lin,Szu-Yuan Li,Chih-Cheng Wu,Po-Hsun Huang,Jaw-Wen Chen,Hsiao-Ya Tsai,Chin-Sung Kuo,Chih-Pei Lin,Ruey-Hsing Chou

doi:10.18632/oncotarget.24290

Abstract

ObjectiveChronic 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.MethodsHuman 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+).ResultsIncubation 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.ConclusionsChronic hyperuricemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC.

Highlights

Hyperuricemia is becoming a critical medical problem, and its prevalence and related comorbidities have dramatically increased in past decades [1]
Chronic hyperuricemia impaired blood flow recovery and endothelial progenitor cells (EPC) mobilization in response to tissue ischemia, and these effects could have occurred through suppression of EPC
After administration of EPC with a high-level Uric acid (UA) medium, sirT1 was significantly downregulated compared to the control, and p16 was upregulated compared to the control. (Figure 2C) These findings suggest that a high concentration of UA induces cellular apoptosis and suppresses EPC proliferation

Summary

Introduction

Hyperuricemia is becoming a critical medical problem, and its prevalence and related comorbidities have dramatically increased in past decades [1]. Some studies have reported that hyperuricemia may be associated with cardiovascular disease, independent of traditional risk factors [7, 8], but others have suggested that this association is confounded by the coexistence of cardiovascular risk factors [9]. An increasing body of evidence suggests elevated serum UA in humans is associated with endothelial dysfunction [10], enhanced systemic inflammation [11], elevated oxidative stress [12], and risk of cardiovascular mortality [13]. A high level of UA should be a crucial mediator associated with reduced vasodilator capacity pro-inflammatory and prothrombotic states, and could be an independent risk factor for cardiovascular disease

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