title: Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation.
abstract: Diabetic cardiomyopathy is related to oxidative stress and correlated with the presence of advanced glycation end products (AGEs). In a clinical setting, AGEs can be detected in patients presenting diabetic cardiomyopathy; however, the underlying mechanism has yet to be elucidated. In our previous study, AGEs increase cell hypertrophy via ERK phosphorylation in a process closely related to ROS production. Thus, we propose that AGEs regulate the antioxidant gene nuclear factor-erythroid 2-related factor (Nrf-2). In H9c2 cells treated with AGEs, the expression of Nrf-2 was reduced; however, ERK phosphorylation was shown to increase. Treatment with H2O2 was also shown to increase Nrf-2 and ERK phosphorylation. In cells pretreatment with ROS scavenger NAC, the effects of H2O2 were reduced; however, the effects of the AGEs remained largely unchanged. Conversely, when cells were pretreated with PD98059 (ERK inhibitor), the expression of Nrf-2 was recovered following treatment with AGEs. Our results suggest that AGEs inhibit Nrf-2 via the ERK pathway; however, this influence is partly associated with ROS. Our finding further indicated that AGEs possess both ROS-dependent and ROS-independent pathways, resulting in a reduction in Nrf-2. This report reveals an important mechanism underlying the regulation of diabetic cardiomyopathy progression by AGEs.
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Tainan, Taiwan; Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan. Electronic address: syko@mail.cjcu.edu.tw.
authors.forename: Shun-Yao
authors.initials: SY
authors.lastname: Ko
authors.affiliation: Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Shu-Shing
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, Collage of Health Science, Tainan, Taiwan; Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Hong-I
authors.initials: HI
authors.lastname: Chen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D058065:Diabetic Cardiomyopathies / Q000378:metabolism; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000975:Antioxidants; D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Advanced glycation end products; Diabetic cardiomyopathy; ERK; Nuclear factor-erythroid 2 related factor; ROS