Prevention of Cyclophilin D-Mediated mPTP Opening Using Cyclosporine-A Alleviates the Elevation of Necroptosis, Autophagy and Apoptosis-Related Markers Following Global Cerebral Ischemia-Reperfusion
Prevention of Cyclophilin D-Mediated mPTP Opening Using Cyclosporine-A Alleviates the Elevation of Necroptosis, Autophagy and Apoptosis-Related Markers Following Global Cerebral Ischemia-Reperfusion
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DOI：
10.1007/s12031-016-0843-3
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发表时间：
2017-01-01
影响因子：
3.1
通讯作者：
Ahmadiani, Abolhassan
中科院分区：
文献类型：
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作者：
Fakharnia, Farinoosh;Khodagholi, Fariba;Ahmadiani, Abolhassan
线粒体通透性转换孔(MPTP)是内膜的一个复杂通道，它的开放导致线粒体肿胀和线粒体膜电位(MMP)的耗散。在这里，我们旨在评估亲环素D(CypD)作为MPTP的重要介体，在全脑缺血再灌注(I/R)损伤之外，在坏死性下垂、自噬和细胞凋亡中的作用。我们发现，虽然脑I/R损伤伴随着线粒体膜丢失、线粒体肿胀和程序性细胞死亡，但环孢素A(CsA)作为CypD的有效抑制剂，可导致部分但显著的坏死下垂标志物RIP1和RIP3以及RIP3下游酶谷氨酸氨连合酶(GLUL)和谷氨酸脱氢酶1(GLUD1)的活性降低。给予CsA也部分减少了自噬相关蛋白。此外，我们还发现，作为细胞凋亡的执行者，CsA可显著降低Bax/Bcl2的比值和caspase-3的活性。综上所述，我们的结果表明，CypD在诱导坏死性下垂和自噬方面起到了部分作用，同时也参与了细胞凋亡的调控。
The mitochondrial permeability transition pore (mPTP) is a complex channel of the inner membrane, the opening of which leads to mitochondrial swelling and dissipation of mitochondrial membrane potential (MMP). Here, we aimed to evaluate the role of the cyclophilin D (CypD) as a prominent mediator of mPTP, on necroptosis and autophagy as well as apoptosis, beyond the global cerebral ischemia-reperfusion (I/R) injury. We showed that while cerebral I/R injury is accompanied by loss of MMP, mitochondrial swelling and programmed cell death, pretreatment with cyclosporine-A (CsA) as a potent inhibitor of CypD, led to partial but significant reduction in necroptosis markers, RIP1 and RIP3 as well as activity of glutamate-ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1), downstream enzymes of RIP3. Administration of CsA also partially decreased autophagy associated proteins. Furthermore, we demonstrated that Bax/Bcl-2 ratio as well as caspase-3 activation, as the executioner of apoptosis, noticeably decreased by CsA pretreatment. Taken together, our results suggest that the CypD alongside the apoptosis regulation plays a partial role in inducing necroptosis and autophagy.