Hypoxia-inducible factor 1a in neutrophils: Impact on myocardial ischemia reperfusion injury

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Perioperative myocardial ischemia is one of the leading causes of death in non-cardiac surgery patients and 3% of patients after non-cardiac surgery experience a myocardial infarction peri-operatively [1]. Mainstay therapies contain a risk for severe bleeding from the surgical site and are often not applicable. Thus, new therapeutic strategies to dampen myocardial ischemia and reperfusion injury could substantially improve perioperative outcomes. Our research focuses on endogenous mechanisms that render myocardial tissue more resistant to ischemia.During ischemia, shifts in the ratio of oxygen supply and demand result in severe tissue hypoxia that persists throughout the reperfusion period. Central to cellular response to hypoxia is the stabilization of the transcription factors hypoxia inducible factor 1 alpha (HIF1a) and hypoxia inducible factor 2 alpha (HIF2a). They appear to be non-redundant in myocardial ischemia reperfusion injury. Our previous studies show that HIF2a reduces infarct sizes when stabilized in cardiomyocytes [2]. Yet, HIF1a stabilization also attenuates myocardial reperfusion injury. The cellular source of HIF1a-elicited cardioprotection remains largely unknown. To address the tissue-specific functions of HIF1a during myocardial ischemia, we deleted HIF1a in different types involved in myocardial ischemia. Since whole-body HIF1a-deficient mice are not viable, we generated animals with a tissue-specific deletion of HIF1a in cardiomyocytes, endothelial or bone-marrow derived inflammatory cells. These animals underwent an in situ model of myocardial ischemia-reperfusion, followed by an assessment of myocardial injury. Interestingly, HIF1a deletion in cardiac myocytes or endothelial did not affect myocardial injury. In contrast to this, HIF1a deletion in bone-marrow derived inflammatory cells increased myocardial injury. This suggests, that HIF1a reduces the cellular-mediated inflammation to myocardial ischemia. Thus, in the present proposal we will investigate, how HIF1a dampens myocardial injury through inflammatory cells and compare its effect to that of HIF2a. We have formulated three specific aims: Specific aim 1: What timeline does HIF1a stabilization follow during myocardial ischemia and reperfusion injury?What is the main cell type stabilizing for HIF1a in the post-ischemic myocardium?Specific aim 2: Does HIF1a interfere with leucocyte recruitment into the post-ischemic myocardium?Does HIF1a reduce the tissue-damaging effects of inflammatory cells?Specific aim 3: Does HIF2a elicits the same cardioprotective effects in inflammatory cells as HIF1a?Which innate immune cells need to stabilize HIF isoforms to protect the myocardium?Is pharmacological stabilization of HIF1a and HIF2a in innate immune cells feasible as a therapy for experimental myocardial ischemia?