HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation

被引：92

作者：

Willam, Carsten ^{[1
]}

Maxwell, Patrick H. ^{[1
]}

Nichols, Lynn ^{[1
]}

Lygate, Craig ^{[1
]}

Tian, Ya Min ^{[1
]}

Bernhardt, Wanja ^{[1
]}

Wiesener, Michael ^{[1
]}

Ratcliffe, Peter J. ^{[1
]}

Eckardt, Kai-Uwe ^{[1
]}

Pugh, Christopher W. ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, Dept Hypertens & Nephrol, D-91054 Erlangen, Germany

来源：

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY | 2006年 / 41卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

hypoxia-inducible factor; hypoxia; prolyl hydroxylase; infarction; histo(path)ology; ischemia;

D O I：

10.1016/j.yjmcc.2006.04.009

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Hypoxia-inducible factor (HIF) regulates expression of genes involved in adaptation to hypoxia and ischemia. Three prolyl hydroxylases (PHD1-3) underlie oxygen-regulated destruction of HIFalpha chains. We have investigated the organ distribution of the PHDs in the rat, their regulation by hypoxia and changes in local expression after experimental myocardial infarction using RNase protection assays, in situ hybridization and immunohistochemistry. mRNAs of all isoforms were detectable in heart, liver, kidney, brain, testis and lung. In normal animals, highest levels for PHD2 mRNA and PHD3 mRNA were found in myocardium, whereas PHD1 mRNA was detected predominantly in the testis. PHD1 mRNA was constitutively expressed. PHD2 mRNA was induced by hypoxia in the liver and PHD3 mRNA in liver, testis and heart. Overall our results show that PHD2 mRNA is ubiquitously expressed in normal animals, in keeping with a general role in oxygen sensing. PHD1 and 3 mRNA distributions suggest particular roles in testis and heart, respectively. In a model of myocardial infarction, in situ hybridization showed periischemic enhancement for PHD2 mRNA and PHD3 mRNA, but not PHD1 mRNA. Immunostaining of PHD2 and 3 in infarcted hearts showed enhanced protein expression, maximal 7 days after infarction. Levels were strongest in regions neighboring areas of HIF staining but also partially overlapped with these zones. Inducibility of PHD2 and 3 by hypoxia and ischemia in vivo has important implications both for the pathophysiology of conditions where oxygen supply is deranged and for attempts to manipulate the HIF system therapeutically. (c) 2006 Elsevier Inc. All rights reserved.

引用

页码：68 / 77

页数：10

共 32 条

[1] Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia [J].

Ang, SO ;

Chen, H ;

Hirota, K ;

Gordeuk, VR ;

Jelinek, J ;

Guan, YL ;

Liu, EL ;

Sergueeva, AI ;

Miasnikova, GY ;

Mole, D ;

Maxwell, PH ;

Stockton, DW ;

Semenza, GL ;

Prchal, JT .

NATURE GENETICS, 2002, 32 (04) :614-621

[2] Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor [J].

Appelhoff, RJ ;

Tian, YM ;

Raval, RR ;

Turley, H ;

Harris, AL ;

Pugh, CW ;

Ratcliffe, PJ ;

Gleadle, JM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) :38458-38465

[3] HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia [J].

Berra, E ;

Benizri, E ;

Ginouvès, A ;

Volmat, V ;

Roux, D ;

Pouysségur, J .

EMBO JOURNAL, 2003, 22 (16) :4082-4090

[4] A conserved family of prolyl-4-hydroxylases that modify HIF [J].

Bruick, RK ;

McKnight, SL .

SCIENCE, 2001, 294 (5545) :1337-1340

[5] Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease [J].

Clifford, SC ;

Cockman, ME ;

Smallwood, AC ;

Mole, DR ;

Woodward, ER ;

Maxwell, PH ;

Ratcliffe, PJ ;

Maher, ER .

HUMAN MOLECULAR GENETICS, 2001, 10 (10) :1029-1038

[6] C-elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation [J].

Epstein, ACR ;

Gleadle, JM ;

McNeill, LA ;

Hewitson, KS ;

O'Rourke, J ;

Mole, DR ;

Mukherji, M ;

Metzen, E ;

Wilson, MI ;

Dhanda, A ;

Tian, YM ;

Masson, N ;

Hamilton, DL ;

Jaakkola, P ;

Barstead, R ;

Hodgkin, J ;

Maxwell, PH ;

Pugh, CW ;

Schofield, CJ ;

Ratcliffe, PJ .

CELL, 2001, 107 (01) :43-54

[7] HIF-1 as a target for drug development [J].

Giaccia, A ;

Siim, BG ;

Johnson, RS .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (10) :803-811

[8] Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation [J].

Hu, CJ ;

Wang, LY ;

Chodosh, LA ;

Keith, B ;

Simon, MC .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (24) :9361-9374

[9] Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor [J].

Ivan, M ;

Haberberger, T ;

Gervasi, DC ;

Michelson, KS ;

Günzler, V ;

Kondo, K ;

Yang, HF ;

Sorokina, I ;

Conaway, RC ;

Conaway, JW ;

Kaelin, WG .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (21) :13459-13464

[10] HIFα targeted for VHL-mediated destruction by proline hydroxylation:: Implications for O2 sensing [J].

Ivan, M ;

Kondo, K ;

Yang, HF ;

Kim, W ;

Valiando, J ;

Ohh, M ;

Salic, A ;

Asara, JM ;

Lane, WS ;

Kaelin, WG .

SCIENCE, 2001, 292 (5516) :464-468

← 1 2 3 4 →