PMID- 20980551
OWN - NLM
STAT- MEDLINE
DCOM- 20110321
LR  - 20220309
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Linking)
VI  - 300
IP  - 2
DP  - 2011 Feb
TI  - Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel 
      therapeutic targets.
PG  - C226-31
LID - 10.1152/ajpcell.00430.2010 [doi]
AB  - A variety of human disorders, e.g., ischemic heart disease, stroke, kidney 
      disease, eventually share the deleterious consequences of a common, hypoxic and 
      oxidative stress pathway. In this review, we utilize recent information on the 
      cellular defense mechanisms against hypoxia and oxidative stress with the hope to 
      propose new therapeutic tools. The hypoxia-inducible factor (HIF) is a key player 
      as it activates a broad range of genes protecting cells against hypoxia. Its 
      level is determined by its degradation rate by intracellular oxygen sensors 
      prolyl hydroxylases (PHDs). There are three different PHD isoforms (PHD1-3). 
      Small molecule PHD inhibitors improve hypoxic injury in experimental animals but, 
      unfortunately, may induce adverse effects associated with PHD2 inhibition, e.g., 
      angiogenesis. As yet, no inhibitor specific for a distinct PHD isoform is 
      currently available. Still, the specific disruption of the PHD1 gene is known to 
      induce hypoxic tolerance, without angiogenesis and erythrocytosis, by 
      reprogramming basal oxygen metabolism with an attendant decreased oxidative 
      stress in hypoxic mitochondria. A specific PHD1 inhibitor might therefore offer a 
      novel therapy against hypoxia. The nuclear factor-erythroid 2 p45-related factor 
      2 (Nrf2) regulates the basal and inducible expression of numerous antioxidant 
      stress genes. Disruption of its gene exacerbates oxidative tissue injury. Nrf2 
      activity is modulated by Kelch-like ECH-associated protein 1 (Keap1), an 
      intracellular sensor for oxidative stress. Inhibitors of Keap 1 may prove 
      therapeutic against oxidative tissue injury.
FAU - Miyata, Toshio
AU  - Miyata T
AD  - United Centers for Advanced Research and Translational Medicine, Tohoku 
      University School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8575, 
      Japan. miyata@med.tohoku.ac.jp
FAU - Takizawa, Shunya
AU  - Takizawa S
FAU - van Ypersele de Strihou, Charles
AU  - van Ypersele de Strihou C
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20101027
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Protease Inhibitors)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Angiogenesis Inducing Agents/therapeutic use
MH  - Animals
MH  - Humans
MH  - Hypoxia/*drug therapy/physiopathology
MH  - Hypoxia-Inducible Factor 1/metabolism
MH  - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Mice
MH  - Mitochondria/metabolism/physiology
MH  - NF-E2-Related Factor 2/agonists/genetics/metabolism
MH  - Oxidative Stress/drug effects/*physiology
MH  - Oxygen/*metabolism
MH  - Procollagen-Proline Dioxygenase/*antagonists & inhibitors
MH  - Protease Inhibitors/therapeutic use
MH  - Rats
EDAT- 2010/10/29 06:00
MHDA- 2011/03/22 06:00
CRDT- 2010/10/29 06:00
PHST- 2010/10/29 06:00 [entrez]
PHST- 2010/10/29 06:00 [pubmed]
PHST- 2011/03/22 06:00 [medline]
AID - ajpcell.00430.2010 [pii]
AID - 10.1152/ajpcell.00430.2010 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2011 Feb;300(2):C226-31. doi: 
      10.1152/ajpcell.00430.2010. Epub 2010 Oct 27.