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

Abstract

Hypoxia-inducible factor (HIF)-1alpha and -2alpha 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-1alpha and -2alpha proteins and target genes, and mRNA levels were determined by RNase protection. Marked nuclear accumulation of HIF-1alpha and -2alpha 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-alpha subunits, but EC more frequently induced HIF-2alpha. A progressive increase of HIF-2alpha but not HIF-1alpha 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-1alpha and -2alpha appears to be complementary rather than solely redundant.

Hypoxia Inducible Factor-2α Stabilization and Maxi-K + Channel β 1 -Subunit Gene Repression by Hypoxia in Cardiac Myocytes

“…25 Figure 4A illustrates that incubation of cells with either Hif-1␣ or Hif-2␣ siRNA resulted in marked (60% to 70%) and selective decrease of the corresponding mRNAs and proteins (see also Online Figure IV). A scramble siRNA had no significant effects on either Hif-1␣ or Hif-2␣ mRNA and proteins ( Figure 4A and Online Figure IV).…”

“…Therefore, it seems that Hif-2␣-dependent genes could have major roles in cardiac preconditioning, at least in the form triggered by sustained (or long-lasting) hypoxia. This observation is appealing because although Hif-1␣ is known to participate in hypoxic/ischemic cardioprotection, 8,25,34 the involvement in this process of exclusive Hif-2␣-dependent genes was not suspected. However, Hif-2␣ has been suggested to contribute to the protective adaptive responses of kidney tissue 10 and neurons 11 to ischemia, and there are data indicating that Hif-2␣ is necessary for the regulation of antioxidant genes.…”

“…43,44 It has been shown that Hif proteins are increased in the periinfarct zone after myocardial infarction, with Hif-2␣ expression occurring in remote areas from the infarct. 9,25 Therefore, it seems that Hif-2␣ has several as yet unknown unique aspects pertinent to ischemia/reperfusion biology in the heart and possibly other organs. It must be stressed that most previous studies have used alternating short-lasting (few minutes) exposures to ischemia/reperfusion 8 and that in our experiments, we exposed the cells to sustained hypoxia (8 to 24 hours).…”

The impact of O2 availability on human cancer

“…The adaptive responses mediated by the HIFs are important for protecting ischemic tissues from injury and activating the HIF pathway selectively in these tissues could provide an important therapeutic intervention [147][148][149] .…”

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…This indicates that HIF-1a may be a fundamental regulator for stem cell migration following MI. Furthermore, accumulation of HIF-1a has been found in ischemic tissue after MI (Jurgensen et al, 2004). On the basis of these findings, enhancement of HIF-1a expression in the ischemic myocardium has been considered as a therapeutic strategy.…”