Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells.
Three HIF-alpha prolyl-4-hydroxylases (PHDs) (named PHD1, PHD2, and PHD3) effect the proteasome-mediated degradation of HIF by catalyzing the hydroxylation of key proline residues in the HIF-1 alpha subunit under normoxic conditions. When oxygen tension is reduced, PHD-mediated hydroxylation cannot occur, HIF-1 alpha accumulates in the nucleus, resulting in HIF-mediated gene transcription. In the present study, the expression and regulation of PHD mRNA and HIF protein expression was examined in human tissues and primary cells of cardiovascular origin. Treatment of human cardiac myocytes, smooth muscle cells, and endothelial cells with hypoxia or CoCl(2), a hypoxia mimic, resulted in a significant time-dependent increase in PHD3, but not PHD1 or PHD2, mRNA levels, which correlated with an increase in HIF-1 alpha protein expression. Overexpression studies revealed that PHD3 levels influence HIF-1 alpha stability in both normoxic and hypoxic conditions, suggesting that PHD3 may participate in a feedback loop controlling HIF activity.
Cioffi
Catherine L
CL
Department of Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, USA. clcioffi@optonline.net
Liu
Xiao Qin
XQ
Kosinski
Penelope A
PA
Garay
Michelle
M
Bowen
Benjamin R
BR
D001483:Base Sequence; D002319:Cardiovascular System / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D005246:Feedback; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D003035:Cobalt; D011393:Procollagen-Proline Dioxygenase; C018021:cobaltous chloride