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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 5, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp044
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

A novel CXCR4 antagonist derived from human SDF-1β enhances angiogenesis in ischemic mice

Yi Tan1,2,*, Yan Li3,*, Jian Xiao1,4, Hongwei Shao5, Chuanlin Ding2,6, Gavin E. Arteel6,7, Keith A. Webster5, Jun Yan2,6, Hong Yu5, Lu Cai 1,2,7,* and Xiaokun Li1,4,*

1 Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, 325035 China
2 Departments of Medicine and Pediatrics, University of Louisville, Louisville, Kentucky, 40202 USA
3 Department of Surgery, University of Louisville, Louisville, Kentucky, 40202 USA
4 Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical College, Wenzhou 325035, China
5 Vascular Biology Institute, University of Miami, Miller School of Medicine, Miami, Florida, 33136 USA
6 James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, 40202 USA
7 Departments of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, 40202 USA

* Corresponding authors: Dr. XiaoKun Li, The Chinese-American Research Institute for Diabetic Complications, Chashan College Park, Wenzhou, Zhejiang Province, 325035, China, Phone: (011 86) 13676701796; Email: xiaokunli{at}163.net Dr. Lu Cai at Departments of Pediatrics, University of Louisville; 570 South Preston Street, Suite 304F, Louisville, KY 40202; Phone: (502) 852-2214 (O), Fax: (502) 852-5634; l0cai001{at}louisville.edu

Aim: The effects on angiogenesis of a novel CXC chemokine receptor 4 (CXCR4) antagonist, SDF-1βP2G, derived from human stromal cell-derived factor-1ß (SDF-1ß), were examined in a model of hind limb ischemia in mice.

Methods: The antagonistic activities of SDF-1βP2G against CXCR4 were evaluated in vitro and in vivo and compared with phosphate-buffered saline and AMD3100 (a small bicyclam antagonist of SDF-1). Angiogenesis, muscle regeneration and the expression of pro-angiogenic factors were evaluated in ischemic gastrocnemius muscles. Distant toxic effects of SDF-1βP2G were evaluated by inflammatory and apoptotic markers.

Results: SDF-1βP2G induced CXCR4 internalization and competitively inhibited the chemotaxis of SDF-1β but did not mediate migration, calcium influx, or the phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in cultured T-lymphoblastic leukaemia cells or H9C2 cells. SDF-1βP2G enhanced blood flow, angiogenesis and muscle regeneration in ischemic hind limbs, and the enhancement was significantly better than that of AMD3100. Markers of angiogenesis and progenitor cell migration, including phosphorylated Akt, vascular endothelial growth factor (VEGF), SDF-1 and CXCR4, were up-regulated by SDF-1βP2G and co-localized with CD31-positive cells. Neutralization of VEGF with its specific antibody abolished SDF-1βP2G-induced blood reperfusion and angiogenesis. No apparent inflammatory and apoptotic effects were found in heart, liver, kidneys and testes after SDF-1βP2G administration.

Conclusion: Our findings indicate that the novel CXCR4 antagonist, SDF-1βP2G, can efficiently enhance ischemic angiogenesis, blood flow restoration and muscle regeneration without apparent adverse effects, most likely through a VEGF-dependent pathway.

Time for primary review: 29 Days

{dagger} Equal contribution to this study


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