Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm
Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm
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DOI：
10.1016/j.ejphar.2009.08.009
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发表时间：
2009-10-12
影响因子：
5
通讯作者：
Tanaka, Toshio
中科院分区：
文献类型：
--
作者：
Shimada, Yasuhito;Tsunoda, Hiroshi;Tanaka, Toshio
脑血管痉挛仍然是蛛网膜下腔出血患者发病率和死亡率的主要原因。血红素氧合酶-1（HO-1）是一种氧化应激诱导酶，对血管和神经系统疾病（包括迟发性脑血管痉挛）具有多种保护作用。在本研究中，静脉内施用（i. v.）在大鼠蛛网膜下腔出血模型中，尼卡地文（1 mg/kg/min，持续2天）可改善迟发性脑血管痉挛，显著协同诱导HO-1蛋白（>2.5倍于蛛网膜下腔出血+生理盐水i. v. '），并引起基底动脉中cGMP积聚的快速增加。在假手术大鼠中，尼卡地文不能诱导HO-1的表达。反义HO-1寡脱氧核苷酸消除了HO-1的诱导和尼卡地文的抗血管痉挛作用。在使用Hela细胞的体外研究中，尼卡地文增强了人HO-1启动子（约4.5 kbp）的活性，该启动子用血液组分氧合血红蛋白预活化以模拟蛛网膜下腔出血的能力。这些结果表明，这种增强HO-1的表达，通过组合病理状态和药理学试剂可能是一种有效的策略，以改善血红素和氧化应激诱导的疾病，如迟发性脑血管痉挛的预后。(C)2009爱思唯尔有限公司版权所有。
Cerebral vasospasm remains a major cause of morbidity and mortality in patients with subarachnoid hemorrhage. Heme oxygenase-1 (HO-1) is an oxidative stress-inducible enzyme with multiple protective functions against vascular and neurological diseases, including delayed cerebral vasospasm. In the present study, intravenous administration (i.v.) of nicaraven (1 mg/kg/min, for 2 days after subarachnoid hemorrhage) ameliorated delayed cerebral vasospasm in rat subarachnoid hemorrhage models, marked synergistic induction of HO-1 protein (>2.5-fold than 'subarachnoid hemorrhage with saline i.v.'), and elicited a rapid increase of cGMP accumulation in the basilar arteries. In the sham-operated rats, nicaraven could not induce HO-1 expression. Antisense HO-1 oligodeoxynucleotides abrogated this HO-1 induction and the antivasospastic effect of nicaraven. In vitro study using Hela cells, nicaraven enhanced the human HO-1 promoter (-4.5 kbp) activity, which was pre-activated with the blood component oxyhemoglobin to mimic the ability of subarachnoid hemorrhage. These results suggest that this enhanced HO-1 expression through a combination pathological state and pharmacological agent could be an effective strategy to improve the prognosis of heme- and oxidative stress-induced diseases, such as delayed cerebral vasospasm. (C) 2009 Elsevier B.V. All rights reserved.