The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning.
The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning.
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DOI：
10.1016/j.exer.2008.11.013
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发表时间：
2009-03
影响因子：
3.4
通讯作者：
Roth, Steven
中科院分区：
文献类型：
--
作者：
Dreixler, John C.;Hemmert, Jonathan W.;Shenoy, Shanti K.;Shen, Yang;Lee, H. Thomas;Shaikh, Afzhal R.;Rosenbaum, Daniel M.;Roth, Steven
缺血预处理（IPC）可诱导视网膜有效的内源性缺血保护作用。蛋白激酶B/Akt是细胞存活因子。基于Akt亚型的不同效应，我们假设Akt是IPC的组成部分。在IPC或通过开放线粒体KATP（mKATP）通道模拟IPC后，使大鼠经历视网膜缺血。检测了使用渥曼青霉素、API-2或小干扰RNA（siRNA）阻断Akt的效果。视网膜电图评估缺血后的功能恢复，TUNEL检测视网膜神经节细胞凋亡。我们研究了Akt激活与IPC的已知引发剂（包括腺苷受体刺激和mKATP通道开放）之间的关系。PI-3激酶抑制剂渥曼青霉素1或4 mg/kg（i. p.），玻璃体中的特异性Akt抑制剂API-2，5-500 μM，或玻璃体内针对Akt 2或-3但不针对Akt 1的siRNA，显著减弱IPC的神经保护作用。针对三种Akt亚型中的任一种的干扰RNA显著但时间依赖性地减弱mKATP通道开放以模拟IPC。腺苷A1受体阻断剂（DPCPX）、A2 a阻断剂（CSC）或mKATP通道阻断剂5-羟基癸酸显著减弱IPC后Akt激活。针对Akt亚型的干扰RNA阻止IPC对缺血后细胞凋亡的改善作用。所有三种Akt亚型均通过IPC或IPC模拟参与功能性视网膜神经保护。Akt是腺苷A1和A2 a受体和mKATP通道开放的下游。结果表明视网膜中存在基于Akt亚型的稳健和冗余的内源性神经保护。
Potent endogenous protection from ischemia can be induced in the retina by ischemic preconditioning (IPC). Protein kinase B/Akt is a cellular survival factor. We hypothesized that Akt was integral to IPC based upon differential effects of Akt subtypes. Rats were subjected to retinal ischemia after IPC or IPC-mimicking by the opening of mitochondrial KATP (mKATP) channels. The effects of blocking Akt using wortmannin, API-2, or small interfering RNA (siRNA) were examined. Electroretinography assessed functional recovery after ischemia, and TUNEL examined retinal ganglion cell apoptosis. We studied the relationship between Akt activation, and known initiators of IPC, including adenosine receptor stimulation and the opening of mKATP channels. The PI-3 kinase inhibitor wortmannin 1 or 4 mg/kg (i.p.), the specific Akt inhibitor API-2, 5-500 μM in the vitreous, or intravitreal siRNA directed against Akt2 or -3, but not Akt1, significantly attenuated the neuroprotective effect of IPC. Interfering RNA against any of the three Akt subtypes significantly but time-dependently attenuated mKATP channel opening to mimic IPC. Adenosine A1 receptor blockade (DPCPX), A2a blockade (CSC), or the mKATP channel blocker 5-hydroxydecanoic acid significantly attenuated Akt activation after IPC. Interfering RNA directed against Akt subtypes prevented the ameliorative effect of IPC on post-ischemic apoptosis. All three Akt subtypes are involved in functional retinal neuroprotection by IPC or IPC-mimicking. Akt is downstream of adenosine A1 and A2a receptors and mKATP channel opening. The results indicate the presence in the retina of robust and redundant endogenous neuroprotection based upon subtypes of Akt.
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影响因子：
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通讯作者：
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