Nuclear transcriptional factors and hypoxia-inducible genes mediate the hepatic vascular adaptive response to chronic hypoxia

Abstract

We determined the hepatic expression of transcriptional factor HIF-1α inhypoxia and genes possessing hypoxia response element (HRE) such as iNOS,VEGF and ET-1 that modulate the vascular response in liver. We also evaluatedthe concomitant expressions of NF-κB and AP-1. Blood and liver samples fromadult SD rats were collected at specific time-points after exposure of animals to10% oxygen for a period of 28 days. Samples from the normoxic and hypoxicrats were analyzed for serum ALT, hematocrit, 8-isoprostane,immunohistochemistry, RT-PCR, Western Blotting and EMSA.Our results showed a significant increase in the hematocrit and asignificant weight loss in the hypoxic rats. The liver morphology and serumALT were normal. Total free 8-isoprostane levels and nitrotyrosine proteinwere not elevated. iNOS mRNA peaked at day 21 whereas eNOS, VEGF andET-1 mRNAs progressively increased from day 7 to day 28 in hypoxic liver.Similar trends were observed at the protein level by Western blotting. HIF-1α,NF-κB and AP-1 were upregulated in hypoxic liver. We conclude that thevascular adaptive ability of the liver in chronic hypoxia triggers compensatorynitric oxide-dependent mechanisms for cell survival towards a vasodilatoryresponse through upregulation of transcription factors, HRE and eNOS genes