title: Lipid peroxidation end product 4-hydroxy-trans-2-nonenal triggers unfolded protein response and heme oxygenase-1 expression in PC12 cells: Roles of ROS and MAPK pathways.
abstract: This study investigates the roles of ROS overproduction and MAPK signaling pathways in the induction of unfolded protein response (UPR) and the expression of Phase II enzymes in response to 4-hydroxy-trans-2-nonenal (4-HNE) in a neuronal-like catecholaminergic PC12 cells. Our results showed that 4-HNE triggered three canonical pathways of UPR, namely IRE1-XBP1, PERK-eIF2α-ATF4 and ATF6, and induced the expression of UPR-targeted genes, GRP78, CHOP, TRB3, PUMA, and GADD34, as well as Phase II enzymes, HO-1 and GCLC. 4-HNE also induced apoptosis, intracellular calcium accumulation, caspase-3 activation, and G0/G1 cell cycle arrest, which was correlated with the increased expression of GADD45α. The addition of tiron, a cellular permeable superoxide scavenger, scavenged 4-HNE-mediated ROS formation, but did not alleviate cytotoxicity, or the expression of UPR-targeted genes or Phase II enzymes, indicating that ROS overproduction per se did not play a major role in 4-HNE-caused deleterious effects. HO-1 expression was attenuated by Nrf2 siRNA and chemical chaperone 4-phenylbutyrate (4-PBA), suggesting HO-1 expression was regulated by Nrf2-ARE, which may work downstream of ER stress. 4-HNE treatment promptly induced ERK, JNK and p38 MAPK activation. Addition of p38 MAPK specific inhibitor SB203580 attenuated HO-1 upregulation, but enhanced expression of CHOP, PUMA and TRB3, and cytotoxicity. These results indicate that 4-HNE-induced transient p38 MAPK activation may serve as an upstream negative regulator of ER stress and confer adaptive cytoprotection against 4-HNE-mediated cell injury.
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors.forename: Meng-Han
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Weng
authors.affiliation: Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors.forename: Lisu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors.forename: Choi-Lan
authors.initials: CL
authors.lastname: Ha
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan. Electronic address: imwu@mail.chna.edu.tw.
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D000447:Aldehydes / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015227:Lipid Peroxidation; D016716:PC12 Cells; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal; C093642:SB 203580; D002118:Calcium
keywords: 4-HNE; ER stress; HO-1; Unfolded protein response; p38 MAPK