Abstract P1042: Endothelial Hif-2α Expression Prevents Against Myocardial Infarction Induced Heart Failure And Cardiac Microvascular Barrier Dysfunction

Abstract

Background: HIF pathway is quickly activated during myocardial ischemia after myocardial infarction(MI), and cardiac microvascular leakage contributes to heart tissue damage. HIF2α isprofoundly expressed in cardiac endothelial cells (ECs) and the embryonic deletion of HIF2Aresults in increased vascular permeability and aberrant ECs behavior. However, the direct roleof endothelial cell-specific HIF2α (ecHIF2α) in ischemic heart disease is not known. Wehypothesized that ecHIF2α expression in response to myocardial infarction (MI) is protectiveagainst heart failure through the reduction of cardiac ECs apoptosis and inflammation. Methods and Results: To address our hypothesis, we generated EC-specific inducible-HIF2α knockout mice (ecHIF2α -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice. To assess the functional role of HIF2α inischemic heart injury, we ligated the proximal left anterior descending coronary artery to induceMI using the same age and gender-matched ecHIF2α -/- and control ( Hif2a flox/flox ) mice. Cardiacfunction was determined by echocardiography after two and four weeks of ligation. Analysis ofechocardiography revealed worsened heart function, and Masson’s Trichrome stain displayedincreased fibrosis in ecHIF2α -/- mice. In vitro , ECIS analysis of isolated cardiac microvascularendothelial cells showed decreased endothelial barrier function in ecHIF2α -/- cells. In addition,hypoxic stimulation reduces the tube formation capacity in ecHIF2α-/- cells and is sensitive tohypoxia-induced early-stage apoptosis. Deletion of HIF2α, as well as its binding partner ARNT,increased the expression of several inflammatory genes, including IL-6. Interestingly,overexpression of ARNT alone abolishes the HIF2α deletion-induced inflammatory geneexpression. IL-6 protein levels in HIF2α deleted human aortic endothelial cells (HAoEC) show asignificant reduction (n=3-5, p<0.001) in ARNT overexpressed ECs. Conclusion: Collectively our data revealed an essential role of endothelial HIF2α/ARNT in maintaining cardiacfunctions by increasing endothelial barrier function and decreasing inflammation. Therefore,HIF2A/ARNT could provide a potential therapeutic target for the treatment of ischemic heartdisease.