凋亡信号调节激酶 1 是慢性脑低灌注引起认知障碍的新的靶标分子。
Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion.
机构信息
From the Department of Pharmacology and Molecular Therapeutics (K.T., N.K., K.U., Y.H., K.K., T.K., D.S., M.J.M., T.N., S.K.-M.) and Department of Cardiovascular Medicine, Faculty of Life Science (K.T., H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Research Fellowship of the Japan Society for the Promotion of Science, Tokyo, Japan (K.T.); Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto, Japan (O.Y.); Department of Neurology, Graduate School of Medicine, Mie University, Tsu, Japan (H.T.); and Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, and Global Center of Excellence (GCOE) Program, The University of Tokyo, Tokyo, Japan (H.I.).
出版信息
Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):616-25. doi: 10.1161/ATVBAHA.113.302440. Epub 2013 Dec 26.
OBJECTIVE
There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions.
APPROACH AND RESULTS
A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1(-/-)) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1(-/-) mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1(-/-) mice. Cerebral nitrotyrosine was increased in wild-type and ASK1(-/-) BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice.
CONCLUSIONS
Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.
目的
目前尚无血管性痴呆的特定治疗或预防策略。脑小血管病的常见病理学——白质病变，是血管性痴呆的主要原因。我们研究了凋亡信号调节激酶 1（ASK1）是否可能是与血脑屏障破坏和白质病变相关的脑低灌注的关键分子。
方法和结果
通过双侧颈总动脉狭窄（BCAS）手术诱导包括胼胝体在内的白质慢性脑低灌注，建立认知障碍的小鼠模型。BCAS 诱导的白质病变导致 C57BL/6J（野生型）小鼠认知能力下降，但 ASK1 缺陷（ASK1(-/-)）小鼠没有。野生型小鼠大脑中磷酸化 ASK1 增加，BCAS 后野生型小鼠胼胝体脑内皮细胞中磷酸化 p38 和肿瘤坏死因子-α表达增加，但 ASK1(-/-)小鼠没有。BCAS 降低了野生型小鼠胼胝体中 Claudin-5 的表达并破坏了血脑屏障，但 ASK1(-/-)小鼠没有。野生型和 ASK1(-/-)BCAS 小鼠的脑硝基酪氨酸增加。野生型小鼠用 NADPH 氧化酶抑制剂处理后，脑磷酸化 ASK1 没有增加。p38 抑制剂和 NADPH 氧化酶抑制剂模拟了 ASK1 缺陷对认知障碍的保护作用。特异性 ASK1 抑制剂可预防 BCAS 小鼠的认知下降。体外氧葡萄糖剥夺和肿瘤坏死因子-α刺激导致来自野生型小鼠的内皮紧密连接破坏，但 ASK1(-/-)小鼠没有。
结论
氧化应激-ASK1-p38 级联反应通过破坏内皮紧密连接在认知障碍的发病机制中起作用。ASK1 可能是治疗慢性脑低灌注引起的认知障碍的有希望的治疗靶点。
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