Ang-1 gene therapy inhibits HIF-1α-prolyl-4-hydroxylase-2, stabilizes HIF-1α expression and normalizes immature vasculature in db/db mice

  1. Jian-Xiong Chen, M.D. (Jian-xiong.chen{at}vanderbilt.edu) and
  2. Amanda Stinnett, B.S.
  1. Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN 37232

    Abstract

    Objective: Diabetic impaired angiogenesis is associated with the impairment of hypoxia-inducible factor (HIF-1α ) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice.

    Research Design and Methods: db/db mice were systemic administration of adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, VEGF, hemeoxygenase-1 (HO-1), eNOS, Akt and HIF-1α-prolyl-4-hydroxylase-2 (PHD2) expression were measured. Vasculature maturation, capillary and arteriole densities, cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium.

    Results: Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared to wild type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling.

    Conclusion: Normalization of immature vasculature by Ang-1 gene therapy may represent a potential novel therapeutic strategy for the treatment of the diabetes-associated impairment of myocardial angiogenesis.

    Footnotes

      • Received April 15, 2008.
      • Accepted September 17, 2008.

    This Article

    1. Diabetes
    1. Online-Only Appendix
    2. All Versions of this Article:
      1. db08-0503v1
      2. 57/12/3335 most recent