Involvement of HIF1α/Reg protein in the regulation of HMGB3 in myocardial infarction

Abstract

AimsMyocardial ischemia and infarction are the number one cause of cardiovascular disease associated mortality. Cardiomyocyte death during ischemia leads to the loss of cardiac tissue and initiates a signaling cascade between the infarct zone and the area at risk of the myocardium. Here, we sought to determine the involvement of one of the damage-associated molecular patterns HMGB3 in myocardial ischemia and infarction. Methods and resultsWe used the left anterior descending coronary artery ligation model to study the involvement of HMGB3 in myocardial ischemia and infarction. Our results indicated the presence of HMGB3 at a low level under normal conditions, while myocardial injury caused a robust increase in HMGB3 levels in the heart. Further, intra-cardiac injection of mabHMGB3 had improved cardiac function at day 3 by downregulating HMGB3 levels. In contrast, injection of recombinant rat HMGB3 for 7 days during the adaptation phase of myocardial ischemia improved cardiac functional parameters by increasing regenerative protein family expression. Further, to mimic the disease condition, neonatal rat ventricle cardiomyocytes and fibroblasts were exposed to hypoxia; we observed a significant upregulation in the HMGB3, HIF1α, and Reg1α levels. Endothelial cells exposed to recombinant HMGB3 increased the tubule length. Further, the mitochondrial oxygen consumption rate was reduced with the acute induction of recombinant HMGB3 on cardiomyocytes and fibroblasts. ConclusionHMGB3 plays a dual role during the progression of myocardial ischemia and infarction. Clinically, post-myocardial infarction HMGB3-induced sterile inflammation needs to be tightly controlled, as it plays both a pro-inflammatory role and improves cardiac function during the cardiac remodeling phase.