title: Naringin protects against anoxia/reoxygenation-induced apoptosis in H9c2 cells via the Nrf2 signaling pathway.
abstract: Naringin (Nar) is a major and active flavanone glycoside derivative of several citrus species. The antioxidant properties of Nar have an important function in its cardioprotective effects in various models. However, the effects of Nar on Nrf2 activation and the expression of its downstream genes in myocardial cells are yet to be elucidated. This study was designed to investigate the protective effects of Nar against anoxia/reoxygenation (A/R)-induced injury in H9c2 cells and determine its effects on the activity of Nrf2 and the expression of phase II antioxidant enzymes. H9c2 cells were pretreated with Nar for 6 h before exposure to A/R. A/R treatment severely injured the H9c2 cells, which was accompanied by apoptosis. Nar also suppressed the A/R-induced mitochondrial membrane depolarization and caspase-3 activation. Nar pretreatment significantly reduced the apoptotic rate by enhancing the endogenous anti-oxidative activity of superoxide dismutase, glutathione peroxidase, and catalase, thereby inhibiting intracellular reactive oxygen species generation. Moreover, the presence of Nar alone in H9c2 cells increased the nuclear translocation of Nrf2 in a dose- and time-dependent manner, as well as consistently increased the protein levels of heme oxygenase (HO-1) and glutamate cysteine ligase (GCLC). Nar increased the phosphorylation of ERK1/2, PKCδ, and AKT. However, the Nar-mediated Nrf2 activation and cardioprotection were abolished through the genetic silencing of Nrf2 by siRNA and partially inhibited by specific inhibitors of ERK1/2, PKCδ, and AKT. Therefore, Nar provided cardioprotection by inducing the phosphorylation of ERK1/2, PKCδ, and AKT, which subsequently activated Nrf2 and its downstream genes.
authors.affiliation: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China. sunxiaoboyzs@163.com.cn sunguibo@126.com.cn.
authors.forename: R C
authors.initials: RC
authors.lastname: Chen
authors.forename: G B
authors.initials: GB
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: H J
authors.initials: HJ
authors.lastname: Zhang
authors.forename: X B
authors.initials: XB
authors.lastname: Sun
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D020868:Gene Silencing; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy*; D008315:Malondialdehyde / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D044950:Flavanones; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D020011:Protective Agents; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C497260:Prkcd protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; C005274:naringin