title: miR-499 protects cardiomyocytes from H 2O 2-induced apoptosis via its effects on Pdcd4 and Pacs2.
abstract: Background microRNAs (miRNAs) are a class of small, non-coding endogenous RNAs that post-transcriptionally regulate some protein-coding genes. miRNAs play an important role in many cardiac pathophysiological processes, including myocardial infarction, cardiac hypertrophy, and heart failure. miR-499, specifically expressed in skeletal muscle and cardiac cells, is differentially regulated and functions in heart development. However, the function of miR-499 in mature heart is poorly understood. Results We report that cardiac-abundant miR-499 could protect neonatal rat cardiomyocytes against H 2O 2-induced apoptosis. Increased miR-499 level favored survival, while decreased miR-499 level favored apoptosis. We identified three proapoptotic protein-coding genes-Pdcd4, Pacs2, and Dyrk2-as targets of miR-499. miR-499 inhibited cardiomyocyte apoptosis through its suppressive effect on Pdcd4 and Pacs2 expression, thereby blocking Bid expression and BID mitochondrial translocation. We also found that H 2O 2-induced phosphorylation of c-Jun transcriptionally upregulated miR-499 expression via binding of phosphorylated c-Jun to the Myh7b promoter. Conclusions Our results revealed that miR-499 played an inhibiting role in the mitochondrial apoptosis pathway, and had protective effects against H 2O 2-induced injury in cardiomyocytes.
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Jiaji
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cardiology; Peking University Third Hospital; Beijing, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Kangtao
authors.initials: K
authors.lastname: Ma
authors.affiliation: Institute of Vascular Medicine; Peking University Third Hospital; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University; Beijing, P.R. China.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology; School of Basic Medical Sciences; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education of China; Peking University, Beijing, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger; D051381:Rats; D017382:Reactive Oxygen Species; D033921:Vesicular Transport Proteins / Q000235:genetics*; D000097603:Dyrk Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D006861:Hydrogen Peroxide; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D033921:Vesicular Transport Proteins; D000097603:Dyrk Kinases; C558425:MIRN499 microRNA, rat; C000594791:Pacs2 protein, rat; C467042:Pdcd4 protein, rat
keywords: BID; PACS2; PDCD4; c-Jun; miR-499; mitochondrial apoptosis pathway