Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model.
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.
['Hinkel|Rabea|R|', 'Lange|Philipp|P|', 'Petersen|Björn|B|', 'Gottlieb|Elena|E|', 'Ng|Judy King Man|JK|', 'Finger|Stefanie|S|', 'Horstkotte|Jan|J|', 'Lee|Seungmin|S|', 'Thormann|Michael|M|', 'Knorr|Maike|M|', 'El-Aouni|Chiraz|C|', 'Boekstegers|Peter|P|', 'Reichart|Bruno|B|', 'Wenzel|Philip|P|', 'Niemann|Heiner|H|', 'Kupatt|Christian|C|']
D000818:Animals D000229:Dependovirus D004195:Disease Models, Animal D015316:Genetic Therapy D005822:Genetic Vectors D051547:Heme Oxygenase-1 D007249:Inflammation D051379:Mice D017202:Myocardial Ischemia D015427:Reperfusion Injury D013552:Swine
adenoassociated virus reperfusion endothelial transgenic cardiomyocyte