Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node

Petkova, M.; Atkinson, A.J.; Yanni, J.; Stuart, L.; Aminu, A.J.; Ivanova, A.D.; Pustovit, K.B.; Geragthy, C.; Feather, A.; Li Ning; Zhang, Y.; Oceandy, D.; Perde, F.; Molenaar, P.; D’Souza, A.; Fedorov, V.V.; Dobrzynski, H.

Авторы: Petkova Maria, Atkinson Andrew J., Yanni Joseph, Stuart Luke, Aminu Abimbola J., Ivanova Alexandra D., Pustovit K.B., Geragthy Connor, Feather Amy, Li Ning, Zhang Yu, Oceandy Delvac, Perde Filip, Molenaar Peter, D’Souza Alicia, Fedorov Vadim V., Dobrzynski Halina
Журнал: Journal of the American Heart Association
Том: 9
Номер: e016590
Год издания: 2020
DOI: 10.1161/jaha.120.016590
Аннотация: BACKGROUND: The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potentialmorphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca2+-handlingproteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible forhuman SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profileof the human SN as compared with that of non-pacemaker atrial muscle.METHODS AND RESULTS: SN and atrial muscle biopsies were obtained from donor or post-mortem hearts (n=10), histology/immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs,Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR-486-3ppredicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization-activated cyclic nucleotide-gated 1), HCN4,voltage-gated calcium channel (Cav)1.3, and Cav3.1. A luciferase reporter gene assay confirmed that miR-486-3p can controlHCN4 expression via its 3′ untranslated region. In ex vivo SN preparations, transfection with miR-486-3p reduced the beatingrate by ≈35±5% (P<0.05) and HCN4 expression (P<0.05).CONCLUSIONS: The human SN possesses a unique pattern of expression of miRs predicted to target functionally importantgenes. miR-486-3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.
Добавил в систему: Иванова Александра Дмитриевна

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Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Nodeстатья

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