Protein kinase A-dependent suppression of reactive oxygen species in transient focal ischemia in adrenomedullin-deficient mice
Protein kinase A-dependent suppression of reactive oxygen species in transient focal ischemia in adrenomedullin-deficient mice
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DOI：
10.1038/jcbfm.2009.92
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发表时间：
2009-11-01
影响因子：
6.3
通讯作者：
Urabe, Takao
中科院分区：
文献类型：
--
作者：
Miyamoto, Nobukazu;Tanaka, Ryota;Urabe, Takao
本研究旨在探讨肾上腺髓质素缺乏对脑梗死的影响，以及肾上腺髓质素与环amp -蛋白激酶A通路调节活性氧（ROS）的关系。肾上腺髓质素杂合型和野生型小鼠局部缺血60分钟。我们使用肾上腺髓质素杂合子小鼠，因为肾上腺髓质素纯合子在子宫内死亡。在缺血后的几个时间点评估梗死体积、神经功能缺损评分和免疫组织化学分析。肾上腺髓质素杂合小鼠的梗死体积和神经功能缺损评分明显更差。肾上腺髓质素杂合小鼠再灌注后，诱导型一氧化氮、氧化性DNA损伤和脂质过氧化显著积累。用蛋白激酶a抑制剂H89治疗野生型小鼠，导致梗死面积增加，神经功能缺损评分和其他参数恶化至与肾上腺髓质素杂合小鼠相当的水平。相比之下，西洛他唑增加了环AMP，挽救了肾上腺髓质素杂合小鼠的神经功能缺陷和ROS积累。本研究表明，肾上腺髓质素下调可导致小鼠短暂局灶性缺血后ROS升高。结果还表明肾上腺髓质素通过环amp -蛋白激酶A通路对缺血性损伤具有重要作用。脑血流与代谢杂志（2009）29,1769-1779；doi: 10.1038 / jcbfm.2009.92;2009年7月1日在线发布
This study was designed to examine the effect of adrenomedullin deficiency on cerebral infarction and the relationship between adrenomedullin and cyclic AMP-protein kinase A pathway in regulating reactive oxygen species (ROS). Adrenomedullin heterozygous and wild-type mice were subjected to 60-mins focal ischemia. We used adrenomedullin heterozygous mice because adrenomedullin homozygotes die in utero. Infarct volume, neurologic deficit scores, and immunohistochemical analyses were evaluated at several time points after ischemia. The infarct volume and neurologic deficit scores were significantly worse in adrenomedullin heterozygous mice. Significant accumulation of inducible nitric oxide, oxidative DNA damage, and lipid peroxidation was noted after reperfusion in adrenomedullin heterozygous mice. Treatment of wild-type mice with H89, a protein kinase A inhibitor, resulted in increased infarct size, and worsening of neurologic deficit score and other parameters to levels comparable to those of adrenomedullin heterozygous mice. In contrast, cilostazol, which increases cyclic AMP, rescued neurologic deficit and ROS accumulation in adrenomedullin heterozygous mice. This study showed that adrenomedullin downregulation results in increase in ROS after transient focal ischemia in mice. The results also indicated that adrenomedullin has an important function against ischemic injury through the cyclic AMP-protein kinase A pathway. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1769-1779; doi:10.1038/jcbfm.2009.92; published online 1 July 2009