Persistent induction of HIF-1alpha and -2alpha in cardiomyocytes and stromal cells of ischemic myocardium.
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.
Jürgensen
Jan Steffen
JS
Department of Nephrology and Medical Intensive Care, Campus Virchow Klinikum, Germany.
Rosenberger
Christian
C
Wiesener
Michael S
MS
Warnecke
Christina
C
Hörstrup
Jan H
JH
Gräfe
Michael
M
Philipp
Sebastian
S
Griethe
Wanja
W
Maxwell
Patrick H
PH
Frei
Ulrich
U
Bachmann
Sebastian
S
Willenbrock
Roland
R
Eckardt
Kai-Uwe
KU
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
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