- 作者: Samuel HH Chan; Enya YH Sun; Alice YW Chang
- 作者服務機構: Center for Translational Research in Biomedical Sciences, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: As the origin of a life-and-death signal detected from systemic arterial
pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect
progressive dysfunction of central cardiovascular regulation during the advancement towards
brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a
suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present
study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a
member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival
and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM
during brain stem death. We further delineated the participation of MAPK signal-interacting
kinase (MNK), a novel substrate of ERK in this process.
Methods: An experimental model of brain stem death that employed microinjection of the
organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of
Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and
biochemical evaluations.
Results: Results from ELISA showed that whereas the total ERK1/2 was not affected,
augmented phosphorylation of ERK1/2 at Thr202 and Tyr204 in RVLM occurred
preferentially during the pro-life phase of experimental brain stem death. Furthermore,
pretreatment by microinjection into the bilateral RVLM of a specific ERK2 inhibitor, ERK
activation inhibitor peptide II (1 nmol); a specific MEK1/2 inhibitor, U0126 (5 pmol); or a
specific MNK1/2 inhibitor, CGP57380 (5 pmol) exacerbated the hypotension and blunted the
augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments
also blocked the upregulated nitric oxide synthase I (NOS I)/protein kinase G (PKG)
signaling, the pro-life cascade that sustains central cardiovascular regulatory functions during
experimental brain stem death.
Conclusions: Our results demonstrated that activation of MEK1/2, ERK1/2 and MNK1/2 in
RVLM plays a preferential pro-life role by sustaining the central cardiovascular regulatory
machinery during brain stem death via upregulation of NOS I/PKG signaling cascade in
RVLM. - 中文關鍵字: --
- 英文關鍵字: --