Persistent induction of HIF‐1α and ‐2α in cardiomyocytes and stromal cells of ischemic myocardium

Hypoxia‐inducible factor (HIF)‐1α and ‐2α are key regulators of the transcriptional response to hypoxia and pivotal in mediating the consequences of many disease states. In the present work, we define their temporo‐spatial accumulation after myocardial infarction and systemic hypoxia. Rats were exposed to hypoxia or underwent coronary artery ligation. Immunohistochemistry was used for detection of HIF‐1α and ‐2α proteins and target genes, and mRNA levels were determined by RNase protection. Marked nuclear accumulation of HIF‐1α and ‐2α occurred after both systemic hypoxia and coronary ligation in cardiomyocytes as well as interstitial and endothelial cells (EC) without pronounced changes in HIF mRNA levels. While systemic hypoxia led to widespread induction of HIF, expression after coronary occlusion occurred primarily at the border of infarcted tissue. This expression persisted for 4 wk, included infiltrating macrophages, and colocalized with target gene expression. Subsets of cells simultaneously expressed both HIF‐α subunits, but EC more frequently induced HIF‐2α. A progressive increase of HIF‐2α but not HIF‐1α occurred in areas remote from the infarct, including the interventricular septum. Cardiomyocytes and cardiac stromal cells exhibit a marked potential for a prolonged transcriptional response to ischemia mediated by HIF. The induction of HIF‐1α and ‐2α appears to be complementary rather than solely redundant.