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Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats

BACKGROUND: Patients with dilated cardiomyopathy, increased ventricular volume, pressure overload or dysynergistic ventricular contraction and relaxation are susceptible to develop serious ventricular arrhythmias (VA). These phenomena are primarily based on a theory of mechanoelectric feedback, whic...

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Autores principales: Xu, Xue, Zhang, Qiang, Song, Huanqiu, Ao, Zhuo, Li, Xiang, Cheng, Cheng, Shi, Maojing, Fu, Fengying, Sun, Chengtao, Liu, Yuansheng, Han, Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304267/
https://www.ncbi.nlm.nih.gov/pubmed/30595983
http://dx.doi.org/10.7717/peerj.6110
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author Xu, Xue
Zhang, Qiang
Song, Huanqiu
Ao, Zhuo
Li, Xiang
Cheng, Cheng
Shi, Maojing
Fu, Fengying
Sun, Chengtao
Liu, Yuansheng
Han, Dong
author_facet Xu, Xue
Zhang, Qiang
Song, Huanqiu
Ao, Zhuo
Li, Xiang
Cheng, Cheng
Shi, Maojing
Fu, Fengying
Sun, Chengtao
Liu, Yuansheng
Han, Dong
author_sort Xu, Xue
collection PubMed
description BACKGROUND: Patients with dilated cardiomyopathy, increased ventricular volume, pressure overload or dysynergistic ventricular contraction and relaxation are susceptible to develop serious ventricular arrhythmias (VA). These phenomena are primarily based on a theory of mechanoelectric feedback, which reflects mechanical changes that produce alterations in electrical activity. However, very few systematic studies have provided evidence of the preventive effects of artemisinin (ART) on VA in response to left ventricle (LV) afterload increases. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate expression of multiple genes by suppressing mRNAs post-transcriptionally. AIMS: The aims of this study were to investigate preventive effects of ART on mechanical VA and the underling molecular mechanisms of differentially expressed miRNAs (DEMs). METHODS: For the study, 70 male Wistar rats were randomly divided into seven groups: group 1 was a control group (sham surgery); group 2 was a model group that underwent transverse aortic constriction (TAC) surgery; groups 3, 4, 5 and 6 were administered ART 75, 150, 300 and 600 mg/kg before TAC surgery, respectively; and group 7 was administered verapamil (VER) 1 mg/kg before TAC surgery. A ventricular arrhythmia score (VAS) was calculated to evaluate preventive effects of ART and VER on mechanical VA. The high throughput sequencing-based approach provided DEMs that were altered by ART pretreatment between group 2 and group 4. All predicted mRNAs of DEMs were enriched by gene ontology (GO) and Kyoto Encyclopedia annotation of Genes and Genomes (KEGG) databases. These DEMs were validated by a real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The average VASs of groups 3, 4, 5, 6 and 7 were significantly reduced compared with those of group 2 (2.70 ± 0.48, 1.70 ± 0.95, 2.80 ± 0.79, 2.60 ± 0.97, 1.40 ± 0.52, vs 3.70 ± 0.67, p < 0.01, respectively). The three top GO terms were neuron projection, organ morphogenesis and protein domain specific binding. KEGG enrichment of the 16 DEMs revealed that MAPK, Wnt and Hippo signaling pathways were likely to play a substantial role in the preventive effects of ART on mechanical VA in response to LV afterload increases. All candidate DEMs with the exception of rno-miR-370-3p, rno-miR-6319, rno-miR-21-3p and rno-miR-204-5p showed high expression levels validated by RT-qPCR. CONCLUSIONS: Artemisinin could prevent mechanical VA in response to LV afterload increases. Validated DEMs could be biomarkers and therapeutic targets of ART regarding its prevention of VA induced by pressure overload. The KEGG pathway and GO annotation analyses of the target mRNAs could indicate the potential functions of candidate DEMs. These results will help to elucidate the functional and regulatory roles of candidate DEMs associated with antiarrhythmic effects of ART.
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spelling pubmed-63042672018-12-28 Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats Xu, Xue Zhang, Qiang Song, Huanqiu Ao, Zhuo Li, Xiang Cheng, Cheng Shi, Maojing Fu, Fengying Sun, Chengtao Liu, Yuansheng Han, Dong PeerJ Bioinformatics BACKGROUND: Patients with dilated cardiomyopathy, increased ventricular volume, pressure overload or dysynergistic ventricular contraction and relaxation are susceptible to develop serious ventricular arrhythmias (VA). These phenomena are primarily based on a theory of mechanoelectric feedback, which reflects mechanical changes that produce alterations in electrical activity. However, very few systematic studies have provided evidence of the preventive effects of artemisinin (ART) on VA in response to left ventricle (LV) afterload increases. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate expression of multiple genes by suppressing mRNAs post-transcriptionally. AIMS: The aims of this study were to investigate preventive effects of ART on mechanical VA and the underling molecular mechanisms of differentially expressed miRNAs (DEMs). METHODS: For the study, 70 male Wistar rats were randomly divided into seven groups: group 1 was a control group (sham surgery); group 2 was a model group that underwent transverse aortic constriction (TAC) surgery; groups 3, 4, 5 and 6 were administered ART 75, 150, 300 and 600 mg/kg before TAC surgery, respectively; and group 7 was administered verapamil (VER) 1 mg/kg before TAC surgery. A ventricular arrhythmia score (VAS) was calculated to evaluate preventive effects of ART and VER on mechanical VA. The high throughput sequencing-based approach provided DEMs that were altered by ART pretreatment between group 2 and group 4. All predicted mRNAs of DEMs were enriched by gene ontology (GO) and Kyoto Encyclopedia annotation of Genes and Genomes (KEGG) databases. These DEMs were validated by a real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: The average VASs of groups 3, 4, 5, 6 and 7 were significantly reduced compared with those of group 2 (2.70 ± 0.48, 1.70 ± 0.95, 2.80 ± 0.79, 2.60 ± 0.97, 1.40 ± 0.52, vs 3.70 ± 0.67, p < 0.01, respectively). The three top GO terms were neuron projection, organ morphogenesis and protein domain specific binding. KEGG enrichment of the 16 DEMs revealed that MAPK, Wnt and Hippo signaling pathways were likely to play a substantial role in the preventive effects of ART on mechanical VA in response to LV afterload increases. All candidate DEMs with the exception of rno-miR-370-3p, rno-miR-6319, rno-miR-21-3p and rno-miR-204-5p showed high expression levels validated by RT-qPCR. CONCLUSIONS: Artemisinin could prevent mechanical VA in response to LV afterload increases. Validated DEMs could be biomarkers and therapeutic targets of ART regarding its prevention of VA induced by pressure overload. The KEGG pathway and GO annotation analyses of the target mRNAs could indicate the potential functions of candidate DEMs. These results will help to elucidate the functional and regulatory roles of candidate DEMs associated with antiarrhythmic effects of ART. PeerJ Inc. 2018-12-20 /pmc/articles/PMC6304267/ /pubmed/30595983 http://dx.doi.org/10.7717/peerj.6110 Text en © 2018 Xu et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Xu, Xue
Zhang, Qiang
Song, Huanqiu
Ao, Zhuo
Li, Xiang
Cheng, Cheng
Shi, Maojing
Fu, Fengying
Sun, Chengtao
Liu, Yuansheng
Han, Dong
Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title_full Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title_fullStr Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title_full_unstemmed Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title_short Effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microRNA expression profiles in Wistar rats
title_sort effects of artemisinin on ventricular arrhythmias in response to left ventricular afterload increase and microrna expression profiles in wistar rats
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304267/
https://www.ncbi.nlm.nih.gov/pubmed/30595983
http://dx.doi.org/10.7717/peerj.6110
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