Rabea Hinkel1, Philipp Lange2, Björn Petersen3, Elena Gottlieb2, Judy King Man Ng4, Stefanie Finger5, Jan Horstkotte2, Seungmin Lee2, Michael Thormann2, Maike Knorr5, Chiraz El-Aouni2, Peter Boekstegers2, Bruno Reichart6, Philip Wenzel5, Heiner Niemann3, Christian Kupatt7. 1. Medizinische Klinik I, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig Maximillian University, Munich, Germany; Medizinische Klinik I, Klinikum Rechts der Isar, Technical University of Munich, and German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany. 2. Medizinische Klinik I, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany. 3. Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut, Mariensee, Germany. 4. Medizinische Klinik I, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany; Medizinische Klinik I, Klinikum Rechts der Isar, Technical University of Munich, and German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany. 5. Department of Medicine 2, Center for Thrombosis and Hemostasis Mainz and German Center for Cardiovascular Research, partner site Rhine Main, Mainz, Germany. 6. Walter-Brendel-Centre for Experimental Medicine, Munich, Germany. 7. Medizinische Klinik I, Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany; Medizinische Klinik I, Klinikum Rechts der Isar, Technical University of Munich, and German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel-Centre for Experimental Medicine, Munich, Germany. Electronic address: christian.kupatt@tum.de.
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.
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 humanheme oxygenase-1 (hHO-1) in attenuating post-ischemic inflammation in a murine and a porcine ischemia/reperfusion model. METHODS:Murineischemia 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.
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