Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model

Rabea Hinkel, Philipp Lange, Björn Petersen, Elena Gottlieb, Judy King Man Ng, Stefanie Finger, Jan Horstkotte, Seungmin Lee, Michael Thormann, Maike Knorr, Chiraz El-Aouni, Peter Boekstegers, Bruno Reichart, Philip Wenzel, Heiner Niemann, Christian Kupatt

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Background Heme oxygenase-1 (HO-1) is an inducible stress-responsive enzyme converting heme to bilirubin, carbon monoxide, and free iron, which exerts anti-inflammatory and antiapoptotic effects. Although efficient cardioprotection after HO-1 overexpression has been reported in rodents, its role in attenuating post-ischemic inflammation is unclear. Objectives This study assessed the efficacy of recombinant adenoassociated virus (rAAV)-encoding human heme oxygenase-1 (hHO-1) in attenuating post-ischemic inflammation in a murine and a porcine ischemia/reperfusion model. Methods Murine ischemia was induced by 45 min of left anterior descending occlusion, followed by 24 h of reperfusion and functional as well as fluorescent-activated cell sorting analysis. Porcine hearts were subjected to 60 min of ischemia and 24h of reperfusion before hemodynamic and histologic analyses were performed. Results Human microvascular endothelial cells transfected with hHO-1 displayed an attenuated interleukin-6 and intercellular adhesion molecule 1 expression, resulting in reduced monocytic THP-1 cell recruitment in vitro. In murine left anterior descending occlusion and reperfusion, the post-ischemic influx of CD45+ leukocytes, Ly-6G+ neutrophils, and Ly-6Chigh monocytes was further exacerbated in HO-1-deficient hearts and reversed by rAAV.hHO-1 treatment. Conversely, in our porcine model of ischemia, the post-ischemic influx of myeloperoxidase-positive neutrophils and CD14+ monocytes was reduced by 49% and 87% after rAAV.hHO-1 transduction, similar to hHO-1 transgenic pigs. Functionally, rAAV.hHO-1 and hHO-1 transgenic left ventricles displayed a smaller loss of ejection fraction than control animals. Conclusions Whereas HO-1 deficiency exacerbates post-ischemic cardiac inflammation in mice, hHO-1 gene therapy attenuates inflammation after ischemia and reperfusion in murine and porcine hearts. Regional hHO-1 gene therapy provides cardioprotection in a pre-clinical porcine ischemia/reperfusion model.

Original languageEnglish
Article number21346
Pages (from-to)154-165
Number of pages12
JournalJournal of the American College of Cardiology
Volume66
Issue number2
DOIs
StatePublished - 14 Jul 2015
Externally publishedYes

Keywords

  • adenoassociated virus
  • cardiomyocyte
  • endothelial
  • reperfusion
  • transgenic

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