HIF-1alpha subunit and vasoactive HIF-1-dependent genes are involved in carbon monoxide-induced cerebral hypoxic stress response.
Hypoxia-inducible transcription factor-1 (HIF-1) is the most important component of cellular and molecular adaptive responses to hypoxia. We aimed to analyze effects of systemic hypoxia and CO exposure on the oxygen-regulated alpha-subunit of HIF-1 and HIF-1-dependent vasoactive target genes in rat brain. Brains of adult Sprague-Dawley rats were investigated after incubation for 3 and 12 h under normoxia, hypoxia (8% O(2)) and CO 0.1% (n = 10 per group). Upon 3 h of exposure, hypoxia and CO-induced accumulation of HIF-1alpha protein in brain homogenates assessed by Western blot analysis. In contrast to hypoxia HIF-1alpha signals decreased markedly during 12 h-exposure to CO. By immunohistochemistry, intensive HIF-1alpha-positive staining was found in neurons of the cortex and hippocampus. Cerebral expression of vasoactive target genes adrenomedullin (ADM) and vascular endothelial growth factor (VEGF) showed up-regulation during both hypoxia and CO exposure indicating functional activation of HIF-1. Hypoxia increased ADM (P < 0.05) and VEGF mRNA levels within 3 h (P < 0.01) which persisted up to 12 h of exposure (ADM, P < 0.05; VEGF, P < 0.001). Similarly, CO inhalation led to early up-regulation of VEGF (3 h: P < 0.05; 12 h: P < 0.01), but a more delayed increase of ADM mRNA levels (3 h: n.s., 12 h: P < 0.01). We suggest that CO-induced oxygen deprivation is a potent stimulus to cerebral HIF-1-regulated hypoxic stress responses even though its effects are more transient than exposure to hypoxia.
Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nuremberg, Loschgestrasse 15, Erlangen, Germany.
S
S
Bani Hashemi
J
J
Braun
W M
WM
Bernhardt
W
W
Rascher
J
J
Dötsch
R
R
Trollmann
D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002248:Carbon Monoxide; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D002534:Hypoxia, Brain / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D053607:Adrenomedullin; D002248:Carbon Monoxide