Cardiovascular Research Advance Access first published online on February 5, 2009
This version [Corrected Proof] published online on February 24, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp044
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A novel CXCR4 antagonist derived from human SDF-1β enhances angiogenesis in ischaemic mice
1 Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Chashan College Park, Wenzhou 325035, China
2 Department of Medicine and Pediatrics, University of Louisville, 570 South Preston Street, Suite 304F, Louisville, KY 40202, USA
3 Department of Surgery, University of Louisville, Louisville, KY 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, FL 33136, USA
6 James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202 USA
7 Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
8 Miami VA HealthCare System, Miami, FL 33125, USA
* Corresponding authors. Tel: +86 136 7670 1796 (X.L.); Tel:+1 502 852 2214; fax: +1 502 852 5634 (L.C.).E-mail address: xiaokunli{at}163.net (X.L.) or l0cai001{at}louisville.edu (L.C.)
Aims: The effects on angiogenesis of a novel CXC chemokine receptor 4 (CXCR4) antagonist, SDF-1βP2G, derived from human stromal cell-derived factor-1β (SDF-1β), were examined in a model of hind limb ischaemia in mice.
Methods and results: 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 ischaemic gastrocnemius muscles. Distant toxic effects of SDF-1βP2G were evaluated by inflammatory and apoptotic markers. 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 in cultured T-lymphoblastic leukaemia cells or H9C2 cells. SDF-1βP2G enhanced blood flow, angiogenesis, and muscle regeneration in ischaemic 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 ischaemic angiogenesis, blood flow restoration, and muscle regeneration without apparent adverse effects, most likely through a VEGF-dependent pathway.
KEYWORDS CXCR4 antagonist; SDF-1; AMD3100; Limb ischaemic injury; Angiogenesis
Time of primary review: 29 days
The first two authors contributed equally to the study.
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