Differential regulation of HIF-1α prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells
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- 作者：Cioffi ; Catherine L. ; Qin Liu ; Xiao ; Kosinski ; Penelope A. ; Garay ; Michelle ; Bowen ; Benjamin R.
- 关键词：Hypoxia ; Hypoxia-inducible transcription factor ; HIF ; Proline 4-hydroxylase ; PHD
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2003
- 出版时间：April 11, 2003
- 年：2003
- 卷：303
- 期：3
- 页码：947-953
- 全文大小：301 K
文摘
Three HIF-α 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-1α subunit under normoxic conditions. When oxygen tension is reduced, PHD-mediated hydroxylation cannot occur, HIF-1α 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 CoCl2, 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-1α protein expression. Overexpression studies revealed that PHD3 levels influence HIF-1α stability in both normoxic and hypoxic conditions, suggesting that PHD3 may participate in a feedback loop controlling HIF activity.