The Buck Institute for Research on Aging, Novato, California, United States of America.
PLoS One. 2012;7(2):e31739. doi: 10.1371/journal.pone.0031739. Epub 2012 Feb 14.
Mitochondria play a critical role in cell survival and death after cerebral ischemia. Uncoupling proteins (UCPs) are inner mitochondrial membrane proteins that disperse the mitochondrial proton gradient by translocating H(+) across the inner membrane in order to stabilize the inner mitochondrial membrane potential (ΔΨ(m)) and reduce the formation of reactive oxygen species. Previous studies have demonstrated that mice transgenically overexpressing UCP2 (UCP2 Tg) in the brain are protected from cerebral ischemia, traumatic brain injury and epileptic challenges. This study seeks to clarify the mechanisms responsible for neuroprotection after transient focal ischemia. Our hypothesis is that UCP2 is neuroprotective by suppressing innate inflammation and regulating cell cycle mediators. PCR gene arrays and protein arrays were used to determine mechanisms of damage and protection after transient focal ischemia. Our results showed that ischemia increased the expression of inflammatory genes and suppressed the expression of anti-apoptotic and cell cycle genes. Overexpression of UCP2 blunted the ischemia-induced increase in IL-6 and decrease in Bcl2. Further, UCP2 increased the expression of cell cycle genes and protein levels of phospho-AKT, PKC and MEK after ischemia. It is concluded that the neuroprotective effects of UCP2 against ischemic brain injury are associated with inhibition of pro-inflammatory cytokines and activation of cell survival factors.
线粒体在脑缺血后细胞存活和死亡中起着关键作用。解偶联蛋白（UCPs）是线粒体内膜蛋白，通过跨线粒体内膜转运 H(+) 来分散线粒体质子梯度，从而稳定线粒体内膜电位（ΔΨ(m)）并减少活性氧的形成。先前的研究表明，在大脑中转基因过表达 UCP2（UCP2 Tg）的小鼠对脑缺血、创伤性脑损伤和癫痫发作具有保护作用。本研究旨在阐明短暂性局灶性脑缺血后神经保护的机制。我们的假设是，UCP2 通过抑制固有炎症和调节细胞周期介质来发挥神经保护作用。PCR 基因芯片和蛋白质芯片用于确定短暂性局灶性脑缺血后的损伤和保护机制。我们的结果表明，缺血增加了炎症基因的表达，抑制了抗凋亡和细胞周期基因的表达。UCP2 的过表达减弱了缺血诱导的 IL-6 增加和 Bcl2 减少。此外，UCP2 增加了缺血后细胞周期基因的表达和磷酸化 AKT、PKC 和 MEK 的蛋白水平。结论是，UCP2 对缺血性脑损伤的神经保护作用与抑制促炎细胞因子和激活细胞存活因子有关。
