Statins, HMG-CoA reductase inhibitors, improve neovascularization by increasing the expression density of CXCR4 in endothelial progenitor cells
Journal
PLoS ONE
Journal Volume
10
Journal Issue
8
Date Issued
2015
Author(s)
Chiang, K.-H.
Cheng W.-L
Shih C.-M
Lin Y.-W
Tsao N.-W
Kao Y.-T
Huang C.-Y
Lin F.-Y.
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. ? 2015 Chiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
SDGs
Other Subjects
atorvastatin; chemokine receptor CXCR4; rosuvastatin; stromal cell derived factor 1alpha; von Willebrand factor; atorvastatin; chemokine receptor CXCR4; hydroxymethylglutaryl coenzyme A reductase inhibitor; messenger RNA; rosuvastatin; angiogenesis; animal cell; animal experiment; animal model; animal tissue; Article; blood flow; bone marrow transplantation; capillary density; cell homing; controlled study; endothelial progenitor cell; human; human cell; in vitro study; in vivo study; limb ischemia; male; mouse; neovascularization (pathology); neovasculogenesis; nonhuman; protein expression; upregulation; animal; cell culture; cell motion; cell proliferation; drug effects; electron spin resonance; endothelial progenitor cell; enzyme immunoassay; flow cytometry; genetics; hindlimb; Institute for Cancer Research mouse; ischemia; metabolism; neovascularization (pathology); pathology; real time polymerase chain reaction; reverse transcription polymerase chain reaction; signal transduction; vascularization; Western blotting; Animals; Atorvastatin Calcium; Blotting, Western; Cell Movement; Cell Proliferation; Cells, Cultured; Electron Spin Resonance Spectroscopy; Endothelial Progenitor Cells; Flow Cytometry; Hindlimb; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoenzyme Techniques; Ischemia; Male; Mice; Mice, Inbred ICR; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rosuvastatin Calcium; Signal Transduction
Type
journal article