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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.

Authors: Dai, KY  Chan, SH  Chang, AY 
Citation: Dai KY, etal., J Biomed Sci. 2010 Sep 7;17:72. doi: 10.1186/1423-0127-17-72.
Pubmed: (View Article at PubMed) PMID:20819234
DOI: Full-text: DOI:10.1186/1423-0127-17-72

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.

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CRRD Object Information
CRRD ID: 10766439
Created: 2016-02-05
Species: All species
Last Modified: 2016-02-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.