Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion.
Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion.
复制标题
腺苷A2A受体缺乏症上调囊蛋白F表达在由慢性脑部灌注诱导的白质病变中。
DOI：
10.1371/journal.pone.0052566
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Duan W;Ran H;Zhou Z;He Q;Zheng J
在以前的研究中，我们已经表明腺苷A2A受体的失活通过增强神经炎症反应而加剧慢性脑低灌注诱导的白色病变（WML）。然而，腺苷A2A受体的作用的分子机制仍然未知。最近的研究表明，半胱氨酸蛋白酶抑制剂F，一种有效的内源性半胱氨酸蛋白酶抑制剂，选择性地表达在免疫细胞中与中枢神经系统疾病的炎性脱髓鞘相关。为了了解半胱氨酸蛋白酶抑制剂F的表达及其在A2 A受体对慢性脑低灌注诱导的WML影响中的潜在作用，我们研究了A2 A受体基因敲除小鼠WML中半胱氨酸蛋白酶抑制剂F的表达，同窝野生型小鼠和野生型小鼠，在慢性脑灌注不足后，每天用A2A受体激动剂CGS21680或CGS21680和A2A受体拮抗剂SCH 58261治疗的2型小鼠。定量PCR和western blot分析结果显示，慢性脑低灌注后，WML中cystatin F mRNA和蛋白表达均显著上调。此外，在mRNA和蛋白质水平上，A2A受体基因敲除小鼠胼胝体中的胱抑素F表达显著增加，而CGS21680处理的小鼠胼胝体中的胱抑素F表达显著降低。此外，SCH 58261抵消了慢性脑低灌注后CGS 21680产生的半胱氨酸蛋白酶抑制剂F表达的减弱。此外，双重免疫荧光染色显示，半胱氨酸蛋白酶抑制剂F与活化的小胶质细胞标志物CD 11b共定位。结论：CystatinF在活化的小胶质细胞中的表达与A2A受体的作用密切相关，可能与病理过程中发生的神经炎症反应有关。
In previous studies, we have shown that the inactivation of the adenosine A2A receptor exacerbates chronic cerebral hypoperfusion-induced white matter lesions (WMLs) by enhancing neuroinflammatory responses. However, the molecular mechanism underlying the effect of the adenosine A2A receptor remains unknown. Recent studies have demonstrated that cystatin F, a potent endogenous cysteine protease inhibitor, is selectively expressed in immune cells in association with inflammatory demyelination in central nervous system diseases. To understand the expression of cystatin F and its potential role in the effect of A2A receptor on WMLs induced through chronic cerebral hypoperfusion, we investigated cystatin F expression in the WMLs of A2A receptor gene knockout mice, the littermate wild-type mice and wild-type mice treated daily with the A2A receptor agonist CGS21680 or both CGS21680 and A2A receptor antagonist SCH58261 after chronic cerebral hypoperfusion. The results of quantitative-PCR and western blot analysis revealed that cystatin F mRNA and protein expression were significantly up-regulated in the WMLs after chronic cerebral hypoperfusion. In addition, cystatin F expression in the corpus callosum was significantly increased in A2A receptor gene knockout mice and markedly decreased in mice treated with CGS21680 on both the mRNA and protein levels. Additionally, SCH58261 counteracted the attenuation of cystatin F expression produced by CGS21680 after chronic cerebral hypoperfusion. Moreover, double immunofluorescence staining revealed that cystatin F was co-localized with the activated microglia marker CD11b. In conclusion, the cystatin F expression in the activated microglia is closely associated with the effect of the A2A receptors, which may be related to the neuroinflammatory responses occurring during the pathological process.
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DOI：
10.1074/jbc.m111.253914
发表时间：
2011-12-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Colbert JD;Matthews SP;Kos J;Watts C
通讯作者：
Watts C
影响因子：
5.4
作者：
Langerholc, T;Zavasnik-Bergant, V;Kos, J
通讯作者：
Kos, J
影响因子：
7
作者：
Heid, CA;Stevens, J;Williams, PM
通讯作者：
Williams, PM
影响因子：
6.4
作者：
Izzotti, Alberto;Pulliero, Alessandra;Fazzi, Elisa
通讯作者：
Fazzi, Elisa
影响因子：
6.5
作者：
Bangert, C;Friedl, J;Kopp, T
通讯作者：
Kopp, T