Non-hypoxic stabilization of HIF-Iα during coordinated interaction between Akt and angiopoietin-1 enhances endothelial commitment of bone marrow stem cells

Vien Khach Lai, Muhammad Rizwan Afzal, Muhammad Ashraf, Shujia Jiang, Husnain Kh Haider

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

We previously reported that mesenchymal stem cells (MSC) co-expressing Akt and angiopoietin-1 (Ang-1) preserved infarcted heart function via angiomyogenesis. The present study determined the mechanism of co-overexpression of Akt and Ang-1 in promoting endothelial commitment of MSC. The cells were transduced with vectors encoding for Akt ( AktMSC), Ang-1 ( Ang-1MSC), and both Akt and Ang-1 ( AAMSC) using Empty vector transduced MSC ( EmpMSC) as control. Molecular studies indicated a coordinated interaction between Akt and Ang-1 in AAMSC and led to non-hypoxic stabilization of hypoxia inducible factor-1α (HIF-Iα) which accentuated under 4-h anoxia. We also observed HIF-Iα dependent induction of hemeoxygenase-1, endothelial specific markers and VEGF in AAMSC. Vascular commitment of AAMSC was confirmed by immunostaining, Western blotting and flow cytometry for endothelial specific early and late markers including Flt1, Flk1, Tie2, VCAM-1, and von Willebrand Factor-VIII (vWF-VIII) in HIF-Iα dependent fashion besides exhibiting higher emigrational activity and angiogenesis in vitro. AAMSC transplanted into rat model of myocardial infarction showed higher Flk1 and Flt1 positivity and also promoted intrinsic Flk1 + and Flt1 + cell mobilization into the infarcted heart. Given the ease of availability of MSC and simplicity of approach to co-overexpress Ang-1 and Akt to enhance their endothelial commitment, the strategy will be significant for cellular angiogenesis to treat ischemic heart.

Original languageEnglish (US)
Pages (from-to)719-730
Number of pages12
JournalJournal of Molecular Medicine
Volume90
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

Keywords

  • Akt-1
  • Angiogenesis
  • Angiopoietin-1
  • Gene therapy
  • Mesenchymal stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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