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

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-6C(high) 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.

• Authors: 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
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 66 Issue 2 Pg. 154-65 (Jul 14 2015) ISSN: 1558-3597 [Electronic] United States
• PMID: 26160631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• HMOX1 protein, human
• Heme Oxygenase-1

Topics

• Animals
• Dependovirus
• Disease Models, Animal
• Genetic Therapy (methods)
• Genetic Vectors
• Heme Oxygenase-1 (genetics)
• Inflammation (prevention & control)
• Mice
• Myocardial Ischemia (complications)
• Reperfusion Injury
• Swine