Abstract 5059: hHO-1 Overexpression in Transgenic Pigs is Cardioprotective After Acute Myocardial Ischemia and Reperfsuion

Abstract

The inducible isoform of heme oxygenase (HO-1) responds to stress, such as hypoxia or cytokine activation, by reducing biliverdin to bilirubin, carbon monoxide (CO) and free iron. These have anti-inflammatory, anti-apoptotic potential and reduce free radical formation. During ischemia and even more during reperfusion these mechanisms play a major role for the extent of injury. Now, we investigated the cardio protective potential of a heme oxygenase-1 overexpression in transgenic pigs after acute myocardial ischemia and reperfusion. Methods: Transgenic pigs were generated through somatic nuclear transfer of the humane heme oxygenase 1 gene. In vivo, pigs (n=4 per group) underwent percutaneous LAD occlusion for 60 min, followed by 24 hours of reperfusion. Ejection fraction was obtained before ischemia and after 24 h of reperfusion. In addition regional myocardial function and infarct size were measured at day 1. PCR was performed to assure the HO-1 over expression in the transgenic pigs. Myeloperoxidase (MPO) levels were obtained to analyze inflammatory cell invasion. Results: The PCR analysis revealed overexpression of hHO-1 mRNA levels in the transgenic pigs compared to the wildtype control group. In vivo, hHO-1 overexpressing pigs a significant better global myocardial function compared to the control group (post-ischemic ejection fraction 41±2 vs. 24±4% in control). The analysis of the regional myocardial function showed an improved function in the infarct area of the transgenic group (50±4 % vs. 28±9% of the normoxic level at rest). Infarct size was reduced in hHO-1 overexpressing pigs, compared to controls (35±4 % vs. 63±4% of the area at risk), The evaluation of the leukocyte influx in the ischemic tissue via MPO assay displayed a clear reduction in the transgenic group compared to control (444±24 vs. 2817±831 in control group). Conclusion: We could demonstrate for the first time the cardioprotective potential of heme oxgenase-1 over expression in a transgenic pig model of ischemia and reperfusion. These results indicate a high therapeutic potential of HO-1 after acute myocardial infarction or other ischemia and reperfusion events (such as organ transplantation).