- 作者: Kuang-Yu Dai; Samuel HH Chan; Alice YW Chang
- 作者服務機構: Center for Translational Research in Biomedical Sciences, Chang Gung Memorial, Hospital-Kaohsiung Medical Center, Taiwan, Republic of China
- 中文摘要: --
- 英文摘要:
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-1α or HIF-1β 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. - 中文關鍵字: --
- 英文關鍵字: --