title: Heme oxygenase-1 regulates the JNK signaling pathway through the MLK3-MKK7-JNK3 signaling module in brain ischemia injury.
abstract: Although previous researches indicated that heme oxygenase-1 (HO-1) plays a conspicuous role in neuronal injury induced by reperfusion following the brain ischemia, reasonable mechanisms for the role of HO-1 are not clear. In this work, we investigated whether HO-1 was involved in the regulation of the c-Jun N-terminal kinase (JNK) signaling pathway and neuronal cell injury induced by the brain ischemia followed by reperfusion. Cobaltic protoporphyrin (CoPP), an activator of HO-1, was administrated to induce the overexpression of HO-1 by intracerebroventricular infusion 20 min before ischemia. The results showed that the combination of HO-1-mixed lineage kinase 3 (MLK3), MLK3-mitogen-activated kinase kinase 7 (MKK7) and MKK7-JNK3 increased to a peak at 6h of reperfusion following 15 min of ischemia induced by four-vessel occlusion in rats, and these effects were downregulated by CoPP. In addition, CoPP could inhibit the activation of JNK3, c-Jun and caspase-3. Furthermore, pretreatment with CoPP significantly increased the survival of neurons after 5 days of reperfusion. In contrast, all of the above effects of CoPP were reversed by zinc protoporphyrin (ZnPP), a selective inhibitor of HO-1. Our results suggested that HO-1 could protect neurons against brain ischemic injury by downregulating the JNK signaling pathway through the MLK3-MKK7-JNK3 signaling module.
authors.affiliation: School of Chemical Engineering, China University of Mining and Technology, PR China.
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Song
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Zong
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Mukasa
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Pei
authors.forename: Jie
authors.initials: J
authors.lastname: Mou
authors.forename: Xiang-Ru
authors.initials: XR
authors.lastname: Wen
authors.forename: Zhi-An
authors.initials: ZA
authors.lastname: Liu
authors.forename: Xian-Yong
authors.initials: XY
authors.lastname: Wei
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D006419:Heme Oxygenase (Decyclizing); D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D048057:Mitogen-Activated Protein Kinase 10; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C491523:Hmox1 protein, rat