Statins, HMG-CoA Reductase Inhibitors, Improve Neovascularization by Increasing the Expression Density of CXCR4 in Endothelial Progenitor Cells.

Kuang-Hsing Chiang,Feng-Yen Lin,Yung-Ta Kao,Chih-Ting Lin,Wan-Li Cheng,Shinn-Chih Wu,Chun-Ming Shih,Yi-Wen Lin,Chun-Yao Huang,Nai-Wen Tsao,Masuko Ushio-Fukai

doi:10.1371/journal.pone.0136405

Kuang-Hsing Chiang, Feng-Yen Lin + Show 9 more

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https://doi.org/10.1371/journal.pone.0136405

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Abstract

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are used to reduce cholesterol biosynthesis in the liver. Accordingly, statins regulate nitric oxide (NO) and glutamate metabolism, inflammation, angiogenesis, immunity and endothelial progenitor cells (EPCs) functions. The function of EPCs are regulated by stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β), etc. Even though the pharmacologic mechanisms by which statins affect the neovasculogenesis of circulating EPCs, it is still unknown whether statins affect the EPCs function through the regulation of CXCR4, a SDF-1 receptor expression. Therefore, we desired to explore the effects of statins on CXCR4 expression in EPC-mediated neovascularization by in vitro and in vivo analyses. In animal studies, we analyzed the effects of atorvastatin or rosuvastatin treatments in recovery of capillary density and blood flow, the expression of vWF and CXCR4 at ischemia sites in hindlimb ischemia ICR mice. Additionally, we analyzed whether the atorvastatin or rosuvastatin treatments increased the mobilization, homing, and CXCR4 expression of EPCs in hindlimb ischemia ICR mice that underwent bone marrow transplantation. The results indicated that statins treatment led to significantly more CXCR4-positive endothelial progenitor cells incorporated into ischemic sites and in the blood compared with control mice. In vivo, we isolated human EPCs and analyzed the effect of statins treatment on the vasculogenic ability of EPCs and the expression of CXCR4. Compared with the control groups, the neovascularization ability of EPCs was significantly improved in the atorvastatin or rosuvastatin group; this improvement was dependent on CXCR4 up-regulation. The efficacy of statins on improving EPC neovascularization was related to the SDF-1α/CXCR4 axis and might be regulated by the NO. In conclusion, atorvastatin and rosuvastatin improved neovascularization in hindlimb ischemia mice; this effect may have been mediated by increased CXCR4 expression in EPCs.

Highlights

There are numerous diseases that can cause endothelial cell damage and atherosclerosis progression, including smoking, diabetes mellitus, dyslipidemia and hypertension
Four weeks after statin administration, the ischemia/normal perfusion ratio in the 8 mg/kg BW atorvastatin or 2 and 4 mg/kg BW rosuvastatin-treated group was higher than that in the control group (Fig 1C). These results indicated that atorvastatin or rosuvastatin treatment enhanced the recovery of capillary density after hindlimb ischemia in ICR mice
We showed that both atorvastatin and rosuvastatin led to up-regulated CXCR4 mRNA expression in human endothelial progenitor cells (EPCs), as well as d the functions of human EPCs, including their tube formation and migration abilities

Summary

Introduction

There are numerous diseases that can cause endothelial cell damage and atherosclerosis progression, including smoking, diabetes mellitus, dyslipidemia and hypertension. Dyslipidemia is the most important risk factor for atherosclerosis [1]. Current evidence suggests that endothelial repair is driven by local cell and by the contribution of circulating cells [3]. Circulating cells with the ability to repair the endothelium are named endothelial progenitor cells (EPCs). The numbers and activities of circulating EPCs are thought to be important determinants of cardiovascular disease [6]. A great deal of evidence has suggested that the management of SDF-1 increases blood flow and perfusion via the recruitment of EPCs. The stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis plays an important role in angiogenesis by recruiting EPCs from the bone marrow [7]. It is clinically important to estimate the bioactivity of EPCs and to find an appropriate intervention for improving EPC function [6]

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