Dynamic regulation of HIF-1 signaling in the rhesus monkey heart after ischemic injury

Abstract

Background: Hypoxia inducible factor-1 (HIF-1) plays a key role in modulating post-infarct healing after myocardial ischemic injury through transcriptional regulation of hundreds of genes involved in diverse cardiac remodeling processes. However, the dynamic changes in HIF-1 target gene expression in the ischemic heart after myocardial infarction (MI) have not been well characterized. Methods: We employed a rhesus monkey model of MI induced by left anterior descending artery ligation and examined the expression pattern of HIF-1 target genes in the ischemic heart at 1, 7, and 28 days after injury by bulk RNA-sequencing analysis. Results: Myocardial transcriptomic analysis demonstrated a temporal-specific regulation of genes associated with the inflammatory response, cell proliferation, fibrosis and mitochondrial metabolism during the pathological progression of MI. HIF-1 target genes involved in processes related to glycolysis, angiogenesis, and extracellular matrix (ECM) remodeling also exhibited distinct expression patterns during MI progression. Copper concentrations were gradually decreased in the heart after ischemic injury, which was positively correlated with the expression of HIF-1-mediated angiogenic and glycolytic genes but negatively correlated with the expression of HIF-1-mediated ECM remodeling genes. Moreover, genes related to intracellular copper trafficking and storage were suppressed along with the loss of myocardial copper in the ischemic heart. Conclusions: This study demonstrated a dynamic, functional-specific regulation of HIF-1 target gene expression during the progression of MI. The fine-tuning of HIF-1 signaling in the ischemic heart may be relate to the alteration in myocardial copper homeostasis. These findings provide transcriptomic insights into the distinct roles of HIF-1 signaling in the heart after ischemic injury, which will help determine the beneficial cutoff point for HIF-1 targeted therapy in ischemic heart diseases.