Abstract Tu136: HIF-1α a novel therapeutic target to reduce Cardiac Ischemia Reperfusion Injury during AMI

Abstract

Acute myocardial infarction (AMI) is a major cause of mortality worldwide. In preclinical models of AMI, using a trans-valvular pump (TVP) to reduce left ventricular (LV) workload for 30 minutes before reperfusion reduces infarct size by 50%. The mechanisms underlying the cardioprotective effect of LV unloading remain poorly understood. Hypoxia inducible factor 1-alpha (HIF-1α) is an oxygen-sensitive transcription factor that activates cardioprotective signaling pathways, improves cell survival and mitochondrial function during myocardial ischemia. We hypothesized that LV unloading limits myocardial injury by activating hypoxia inducible factor 1-a (HIF-1α). To explore the effect of LV unloading on HIF-1α stabilization during ischemia, we performed left anterior descending artery (LAD) occlusion for a total of 120 minutes in adult swine in the presence and absence of LV unloading and further 180 minutes of reperfusion was performed following 120 minutes of LAD occlusion. Trans-valvular unloading activation significantly decreased infarct size both during ischemia (IS/AAR: 4.78±4 % vs 1.5±3%) and post reperfusion when compared ischemia alone and IR alone groups (36.04±8.39 % vs 16.02±3.52 %, p<0.0001) respectively. Interestingly, HIF-1α stabilization is significantly reduced with LV unloading during ischemia and significantly increased post reperfusion in the infarct zone of the swine model of AMI. To test whether HIF1a is necessary for cardioprotection with LV unloading, adult swine were treated with intracoronary delivery of the HIF-1α inhibitor (2-methoxyestradiol; 2ME) before reperfusion. Compared to TVP activation for 30 minutes before reperfusion, addition of 2ME abolished the cardioprotective effect of TVP resulting in increased infarct size (16.03% vs 35.86% p<0.03) and decreased HIF-1a stabilization. Stabilizing HIF-1α post-reperfusion by using a well know HIF-1a stabilizing agent Roxadustat, immediately before reperfusion significantly decreased infarct size in both with and without TVP groups compared to IRI alone. Treatment with Roxadustat also preserved mitochondrial function and increased RISK signaling. We report the novel finding that stabilizing HIF-1a activity before reperfusion plays a critical role in reducing Infarct size in preclinical model of AMI.