PMID- 20819234
OWN - NLM
STAT- MEDLINE
DCOM- 20101028
LR  - 20211020
IS  - 1423-0127 (Electronic)
IS  - 1021-7770 (Print)
IS  - 1021-7770 (Linking)
VI  - 17
IP  - 1
DP  - 2010 Sep 7
TI  - Heme oxygenase-1 plays a pro-life role in experimental brain stem death via 
      nitric oxide synthase I/protein kinase G signaling at rostral ventrolateral 
      medulla.
PG  - 72
LID - 10.1186/1423-0127-17-72 [doi]
AB  - BACKGROUND: Despite its clinical importance, a dearth of information exists on 
      the cellular and molecular mechanisms that underpin brain stem death. A suitable 
      neural substrate for mechanistic delineation on brain stem death resides in the 
      rostral ventrolateral medulla (RVLM) because it is the origin of a life-and-death 
      signal that sequentially increases (pro-life) and decreases (pro-death) to 
      reflect the advancing central cardiovascular regulatory dysfunction during the 
      progression towards brain stem death in critically ill patients. The present 
      study evaluated the hypothesis that heme oxygnase-1 (HO-1) may play a pro-life 
      role as an interposing signal between hypoxia-inducible factor-1 (HIF-1) and 
      nitric oxide synthase I (NOS I)/protein kinase G (PKG) cascade in RVLM, which 
      sustains central cardiovascular regulatory functions during brain stem death. 
      METHODS: We performed cardiovascular, pharmacological, biochemical and confocal 
      microscopy experiments in conjunction with an experimental model of brain stem 
      death that employed microinjection of the organophosphate insecticide mevinphos 
      (Mev; 10 nmol) bilaterally into RVLM of adult male Sprague-Dawley rats. RESULTS: 
      Western blot analysis coupled with laser scanning confocal microscopy revealed 
      that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons 
      occurred preferentially during the pro-life phase of experimental brain stem 
      death and was antagonized by immunoneutralization of HIF-1alpha or HIF-1beta in RVLM. On 
      the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested 
      insignificant changes during both phases. Furthermore, immunoneutralization of 
      HO-1 or knockdown of ho-1 gene in RVLM blunted the augmented life-and-death 
      signals exhibited during the pro-life phase. Those pretreatments also blocked the 
      upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS 
      II/peroxynitrite cascade in RVLM. CONCLUSIONS: We conclude that transcriptional 
      upregulation of HO-1 on activation by HIF-1 in RVLM plays a preferential pro-life 
      role by sustaining central cardiovascular regulatory functions during brain stem 
      death via upregulation of NOS I/PKG signaling pathway. Our results further showed 
      that the pro-dead NOS II/peroxynitrite cascade in RVLM is not included in this 
      repertoire of cellular events.
FAU - Dai, Kuang-Yu
AU  - Dai KY
AD  - Center for Translational Research in Biomedical Sciences, Chang Gung Memorial, 
      Hospital-Kaohsiung Medical Center, Kaohsiung County 83301, Taiwan.
FAU - Chan, Samuel Hh
AU  - Chan SH
FAU - Chang, Alice Yw
AU  - Chang AY
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100907
PL  - England
TA  - J Biomed Sci
JT  - Journal of biomedical science
JID - 9421567
RN  - 0 (HIGD1A protein, human)
RN  - 0 (Insecticides)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Oligonucleotides)
RN  - 7786-34-7 (Mevinphos)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Blotting, Western
MH  - Brain Death/metabolism/*physiopathology
MH  - Cyclic GMP-Dependent Protein Kinases/metabolism
MH  - Fluorescent Antibody Technique
MH  - Gene Knockdown Techniques
MH  - Heme Oxygenase-1/genetics/*metabolism
MH  - Insecticides/administration & dosage/*toxicity
MH  - Intracellular Signaling Peptides and Proteins
MH  - Male
MH  - Medulla Oblongata/cytology/*drug effects
MH  - Mevinphos/administration & dosage/*toxicity
MH  - Microscopy, Confocal
MH  - Mitochondrial Proteins
MH  - Neoplasm Proteins/metabolism
MH  - Nitric Oxide Synthase Type I/metabolism
MH  - Oligonucleotides/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*physiology
PMC - PMC2941487
EDAT- 2010/09/08 06:00
MHDA- 2010/10/29 06:00
PMCR- 2010/09/07
CRDT- 2010/09/08 06:00
PHST- 2010/07/27 00:00 [received]
PHST- 2010/09/07 00:00 [accepted]
PHST- 2010/09/08 06:00 [entrez]
PHST- 2010/09/08 06:00 [pubmed]
PHST- 2010/10/29 06:00 [medline]
PHST- 2010/09/07 00:00 [pmc-release]
AID - 1423-0127-17-72 [pii]
AID - 10.1186/1423-0127-17-72 [doi]
PST - epublish
SO  - J Biomed Sci. 2010 Sep 7;17(1):72. doi: 10.1186/1423-0127-17-72.