title: Overexpression of miR-200a protects cardiomyocytes against hypoxia-induced apoptosis by modulating the kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 signaling axis.
abstract: The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis plays an important role in regulating oxidative stress in ischemic cardiomyocytes. Targeting Keap1 in order to promote Nrf2 activation is considered a potential method for protecting cardiomyocytes against ischemic injury. In recent years, microRNAs (miRNAs or miRs) have emerged as powerful tools for controlling gene expression. The present study aimed to determine whether Keap1-Nrf2 was regulated by specific miRNAs in cardiomyocytes under hypoxic conditions. We demonstrated that miR-200a was significantly downregulated in ischemic myocardial tissues and hypoxic cardiomyocytes. The overexpression of miR-200a was found to protect cardiomyocytes from hypoxia-induced cell damage and the excessive production of reactive oxygen species. Through bioinformatics analysis and a dual-luciferase report assay, miR-200a was found to interact with the 3'-untranslated region of Keap1, the native regulator of Nrf2. Reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-200a negatively regulated the expression of Keap1. The overexpression of miR-200a significantly increased the nuclear translocation of Nrf2 as well as downstream antioxidant enzyme gene expression. The inhibition of miR-200a displayed the opposite effects. Restoring the expression of Keap1 significantly abrogated the protective effect of miR‑200a. Taken together, these findings indicate that the suppression of Keap1 by miR-200a exerted a cardioprotective effect against hypoxia-induced oxidative stress and cell apoptosis, and suggest that the activation of Nrf2 signaling by miR‑200a represents a novel and promising therapeutic strategy for the treatment of ischemic heart disease.
authors: Department of Cardiology 3, Xianyang Central Hospital, Xianyang, Shaanxi 712000, P.R. China.
authors: Xiaoxia
authors: X
authors: Sun
authors: Department of Cardiology 3, Xianyang Central Hospital, Xianyang, Shaanxi 712000, P.R. China.
authors: Hong
authors: H
authors: Zuo
authors: Department of Endocrinology, Xianyang Central Hospital, Xianyang, Shaanxi 712000, P.R. China.
authors: Chunmei
authors: C
authors: Liu
authors: Department of Endocrinology, Xianyang Central Hospital, Xianyang, Shaanxi 712000, P.R. China.
authors: Yafeng
authors: Y
authors: Yang
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001483:Base Sequence; D002316:Cardiotonic Agents / Q000378:metabolism*; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D000072019:Kelch-Like ECH-Associated Protein 1; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species