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

Yi Tan, Yan Li, Jian Xiao, Hongwei Shao, Chuanlin Ding, Gavin E. Arteel, Keith A. Webster, Jun Yan, Hong Yu, Lu Cai, Xiaokun Li

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

AimsThe 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 resultsThe 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.ConclusionOur 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.

Original languageEnglish (US)
Pages (from-to)513-521
Number of pages9
JournalCardiovascular Research
Volume82
Issue number3
DOIs
StatePublished - Jun 1 2009

Keywords

  • AMD3100
  • Angiogenesis
  • CXCR4 antagonist
  • Limb ischaemic injury
  • SDF-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Fingerprint Dive into the research topics of 'A novel CXCR4 antagonist derived from human SDF-1β enhances angiogenesis in ischaemic mice'. Together they form a unique fingerprint.

  • Cite this

    Tan, Y., Li, Y., Xiao, J., Shao, H., Ding, C., Arteel, G. E., Webster, K. A., Yan, J., Yu, H., Cai, L., & Li, X. (2009). A novel CXCR4 antagonist derived from human SDF-1β enhances angiogenesis in ischaemic mice. Cardiovascular Research, 82(3), 513-521. https://doi.org/10.1093/cvr/cvp044