title: Downregulation of miR-133 via MAPK/ERK signaling pathway involved in nicotine-induced cardiomyocyte apoptosis.
abstract: Tobacco smoking is a risk factor for many diseases, and nicotine is a major component of tobacco. Our previous work revealed that nicotine can induce myocardial fibrosis. This study aimed to investigate whether nicotine can induce cardiomyocyte apoptosis and to explore the mechanisms involved. Cardiomyocytes were exposed to different nicotine concentrations for 48 h. MTT assay showed that the viability of cardiomyocytes was significantly inhibited by nicotine in a dose- and time-dependent manner. Loss of mitochondrial membrane potential, nuclear and DNA defragmentation determined by TUNEL and ELISA assays, and morphological alterations all revealed the pro-apoptotic property of nicotine. Meanwhile, miR-133, a muscle-specific microRNA, was markedly downregulated by nicotine. Consistently, caspase-9, a target gene for miR-133, was significantly upregulated, leading to an increase in caspase-3, in nicotine-treated cardiomyocytes compared to non-treated cells. Furthermore, ERK1/2 protein levels were considerably downregulated, along with reduction of serum response factor (SRF), which is a downstream target protein of ERK1/2 and an upstream transactivator of miR-133 as well. Our findings therefore revealed that inhibition of the ERK1/2-SRF-miR-133 signaling pathway to increase caspases-9 and -3 is a novel mechanism for nicotine to induce cardiomyocyte apoptosis and these tobacco smokers.
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, No.157 Baojian Road, Harbin, Heilongjiang Province, 150081, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Chaoqian
authors.initials: C
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Shuxuan
authors.initials: S
authors.lastname: Wang
authors.forename: Xuehui
authors.initials: X
authors.lastname: Xiong
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
authors.forename: Ruixue
authors.initials: R
authors.lastname: Zhang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D035683:MicroRNAs / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026362:Serum Response Factor / Q000378:metabolism
chemical_list: C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D026362:Serum Response Factor; D009538:Nicotine; D053148:Caspase 3; D053453:Caspase 9