title: Persistent induction of HIF-1alpha and -2alpha 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.
authors.affiliation: Department of Nephrology and Medical Intensive Care, Campus Virchow Klinikum, Germany.
authors.forename: Jan Steffen
authors.initials: JS
authors.lastname: Jürgensen
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenberger
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
authors.forename: Christina
authors.initials: C
authors.lastname: Warnecke
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hörstrup
authors.forename: Michael
authors.initials: M
authors.lastname: Gräfe
authors.forename: Sebastian
authors.initials: S
authors.lastname: Philipp
authors.forename: Wanja
authors.initials: W
authors.lastname: Griethe
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Ulrich
authors.initials: U
authors.lastname: Frei
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Roland
authors.initials: R
authors.lastname: Willenbrock
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D051272:Glucose Transporter Type 1; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017154:Stromal Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051272:Glucose Transporter Type 1; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1