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SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway.
Biomed Pharmacother. 2019 Feb; 110:431-439.BP

Abstract

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Wang S
Department of Environment Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
Guo X
State Key Lab of NBC Protection for Civilian, Research Institute of Chemical Defense, No. 1 Huaiyin Road, Beijing, 102205, China.
Long CL
Department of Environment Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China; The 307 Military Hospital, Academy of Military Medical Sciences, Beijing, 100850, China.
Li C
Department of Environment Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China.
Zhang YF
Department of Environment Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China; The 307 Military Hospital, Academy of Military Medical Sciences, Beijing, 100850, China.
Wang J
Department of Environment Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin, 300050, China. Electronic address: 13389990368@163.com.
Wang H
The 307 Military Hospital, Academy of Military Medical Sciences, Beijing, 100850, China; Cardiovascular Drug Research Center, Thadweik Academy of Medicine, Beijing, 100039, China. Electronic address: wh9588@sina.com.

MeSH

Allyl CompoundsAnimalsCells, CulturedDose-Response Relationship, DrugEndothelin-1Endothelium, VascularHEK293 CellsHeart FailureHumansKATP ChannelsMicroRNAsPropylaminesRatsRats, WistarSignal TransductionSulfonylurea Receptors

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30530045

Citation

Wang, Shang, et al. "SUR2B/Kir6.1 Channel Openers Correct Endothelial Dysfunction in Chronic Heart Failure Via the miR-1-3p/ET-1 Pathway." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 110, 2019, pp. 431-439.
Wang S, Guo X, Long CL, et al. SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway. Biomed Pharmacother. 2019;110:431-439.
Wang, S., Guo, X., Long, C. L., Li, C., Zhang, Y. F., Wang, J., & Wang, H. (2019). SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 110, 431-439. https://doi.org/10.1016/j.biopha.2018.11.135
Wang S, et al. SUR2B/Kir6.1 Channel Openers Correct Endothelial Dysfunction in Chronic Heart Failure Via the miR-1-3p/ET-1 Pathway. Biomed Pharmacother. 2019;110:431-439. PubMed PMID: 30530045.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway. AU - Wang,Shang, AU - Guo,Xuan, AU - Long,Chao-Liang, AU - Li,Chao, AU - Zhang,Yan-Fang, AU - Wang,Jing, AU - Wang,Hai, Y1 - 2018/12/05/ PY - 2018/09/04/received PY - 2018/11/26/revised PY - 2018/11/27/accepted PY - 2018/12/12/pubmed PY - 2019/4/23/medline PY - 2018/12/12/entrez KW - Chronic heart failure KW - Endothelial function KW - Iptakalim KW - Natakalim KW - SUR2B/Kir6.1 channel KW - miRNA SP - 431 EP - 439 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed Pharmacother VL - 110 N2 - The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3' untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3' UTR 158-165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel's activity against chronic heart failure. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/30530045/SUR2B/Kir6_1_channel_openers_correct_endothelial_dysfunction_in_chronic_heart_failure_via_the_miR_1_3p/ET_1_pathway_ DB - PRIME DP - Unbound Medicine ER -