title: Heme oxygenase-1 protects spinal cord neurons from hydrogen peroxide-induced apoptosis via suppression of Cdc42/MLK3/MKK7/JNK3 signaling.
abstract: The mechanisms by which oxidative stress induces spinal cord neuron death has not been completely understood. Investigation on the molecular signal pathways involved in oxidative stress-mediated neuronal death is important for development of new therapeutics for oxidative stress-associated spinal cord disorders. In current study we examined the role of heme oxygenase-1 (HO-1) in the modulation of MLK3/MKK7/JNK3 signaling, which is a pro-apoptotic pathway, after treating primary spinal cord neurons with H2O2. We found that MLK3/MKK7/JNK3 signaling was substantially activated by H2O2in a time-dependent manner, demonstrated by increase of activating phosphorylation of MLK3, MKK7 and JNK3. H2O2also induced expression of HO-1. Transduction of neurons with HO-1-expressing adeno-associated virus before H2O2treatment introduced expression of exogenous HO-1 in neurons. Exogenous HO-1 reduced phosphorylation of MLK3, MKK7 and JNK3. Consistent with its inhibitory effect on MLK3/MKK7/JNK3 signaling, exogenous HO-1 decreased H2O2-induced neuronal apoptosis and necrosis. Furthermore, we found that exogenous HO-1 inhibited expression of Cdc42, which is crucial for MLK3 activation. In addition, HO-1-induced down-regulation of MLK3/MKK7/JNK3 signaling might be related to up-regulation of microRNA-137 (mir-137). A mir-137 inhibitor alleviated the inhibitory effect of HO-1 on JNK3 activation. This inhibitor also increased neuronal death even when exogenous HO-1 was expressed. Therefore, our study suggests a novel mechanism by which HO-1 exerted its neuroprotective efficacy on oxidative stress.
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, 34 North Zhongshan Road, Quanzhou, 362000, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, The Second Hospital of Fuzhou Affiliated to Xiamen University, Fuzhou, 350007, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Orthopedic Surgery, The People's Hospital of Guizhou Province, Guiyang, 550002, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350004, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Neurology and Institute of Neurology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350004, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, 34 North Zhongshan Road, Quanzhou, 362000, China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350004, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Lan
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, 34 North Zhongshan Road, Quanzhou, 362000, China.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, 34 North Zhongshan Road, Quanzhou, 362000, China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Fujian Medical University, 34 North Zhongshan Road, Quanzhou, 362000, China. okoklwp@126.com.
authors.forename: Wenping
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D048688:MAP Kinase Kinase 7 / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D048057:Mitogen-Activated Protein Kinase 10 / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology*; D014161:Transduction, Genetic; D020764:cdc42 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D006419:Heme Oxygenase (Decyclizing); D006861:Hydrogen Peroxide; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D048057:Mitogen-Activated Protein Kinase 10; D011993:Recombinant Fusion Proteins; D020764:cdc42 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C000595679:MIRN137 microRNA, rat; C491523:Hmox1 protein, rat
keywords: Apoptosis; Cell signaling; Mir-137; Spinal cord injury