Angiogenetic Potential of Ad2/Hif-1α/Vp16 after Regional Application in a Preclinical Pig Model of Chronic Ischemia

Rabea      Hinkel; Corinna      Lebherz; Maria      Fydanaki; Alexander      Wuchrer; Chiraz      El-Aouni; Michael      Thormann; Eckart      Thein; Christian      Kupatt; Peter      Boekstegers

Abstract

Hif-1α, a master regulator of ischemia-responsive gene induction, controls pro-angiogenic gene expression of VEGF-A, flt-1, IGF-1 and erythropoietin, rendering its overexpression an attractive tool for therapeutic neovascularization. Utilizing an adenoviral vector system, we investigated the efficacy of selective pressure-regulated venous retroinfusion of an enhanced Hif-1α mutant (Hif-1α/VP16) in a randomized investigator-blinded study. Methods: Pigs were subjected to percutaneous implantation of a reduction-stent into the circumflex artery, leading to progressive stenosis and complete occlusion at day 28. Selective pressure-regulated retroinfusion of the great cardiac vein was performed at day 28 for regional delivery of either saline or empty vector or Ad2/Hif-1α/VP16. Collateral growth and global myocardial function were obtained by fluoroscopy, whereas regional blood flow and regional myocardial function were assessed by fluorescent microsphere analysis and sonomicrometry, respectively. Capillary density in the ischemic myocardium was analyzed by PECAM-1 staining. Results: Compared to saline and Ad empty vector controls, overexpression of Hif-1α in the ischemic region induced an increase of small (capillary) and large (collateral) vessels, resulting in an improved perfusion of the ischemic myocardium. Concomitantly, an ischemia induced loss of myocardial function (hibernating myocardium) was resolved only after transfection with the Hif 1-α transgene, but not the empty vector or saline control. Conclusion: Retroinfusion of Ad2/Hif-1α/VP16, combining a master pro-angiogenic protein with regional myocardial application, may offer an efficient approach to cardiac gene therapy of chronic ischemic cardiomyopathy.

Keywords: Angiogenesis, arteriogenesis, chronic ischemia, hif-1 alpha, adenovirus, retroinfusion

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