title: Overexpression of mitochondrial uncoupling protein 2 inhibits inflammatory cytokines and activates cell survival factors after cerebral ischemia.
abstract: 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.
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Haines
authors.forename: P Andy
authors.initials: PA
authors.lastname: Li
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007473:Ion Channels / Q000235:genetics* / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D018696:Neuroprotective Agents; D000071246:Uncoupling Protein 2
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2