Silencing miR-370-3p rescues funny current and sinus node function in heart failure

Joseph Yanni Gerges; Alicia D'Souza; Yanwen Wang; Ning Li; Brian J Hansen; Stanislav   Zakharkin; Matthew Smith; Christina Hayward; Bryan A  Whitson; Peter J. Mohler; Paul M L Janssen; Leo Zeef; Moinuddin Choudhury; Min Zi; Xue Cai; Sunil Logantha; Shu Nakao; Andrew Atkinson; Maria Petkova; Ursula Doris; Jonathan Ariyaratnam; Elizabeth Cartwright; Sam Griffiths-Jones; George Hart; Vadim V. Federov; Delvac Oceandy; Halina Dobrzynski; Mark Boyett

doi:10.1038/s41598-020-67790-0

Silencing miR-370-3p rescues funny current and sinus node function in heart failure

Joseph Yanni Gerges, Alicia D'Souza, Yanwen Wang, Ning Li, Brian J Hansen, Stanislav Zakharkin, Matthew Smith, Christina Hayward, Bryan A Whitson, Peter J. Mohler, Paul M L Janssen, Leo Zeef, Moinuddin Choudhury, Min Zi, Xue Cai, Sunil Logantha, Shu Nakao, Andrew Atkinson, Maria Petkova, Ursula DorisJonathan Ariyaratnam, Elizabeth Cartwright, Sam Griffiths-Jones, George Hart, Vadim V. Federov, Delvac Oceandy, Halina Dobrzynski, Mark Boyett

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Abstract

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.

Original language	English
Article number	11279
Journal	Scientific Reports
Volume	10
DOIs	https://doi.org/10.1038/s41598-020-67790-0
Publication status	Published - 9 Jul 2020

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Yanni Gerges, J., D'Souza, A., Wang, Y., Li, N., Hansen, B. J., Zakharkin, S., Smith, M., Hayward, C., Whitson, B. A., Mohler, P. J., Janssen, P. M. L., Zeef, L., Choudhury, M., Zi, M., Cai, X., Logantha, S., Nakao, S., Atkinson, A., Petkova, M., ... Boyett, M. (2020). Silencing miR-370-3p rescues funny current and sinus node function in heart failure. Scientific Reports, 10, [11279]. https://doi.org/10.1038/s41598-020-67790-0

@article{e97bc0594ce94ab0be21b5fcd8cfbb2c,

title = "Silencing miR-370-3p rescues funny current and sinus node function in heart failure",

abstract = "Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.",

author = "{Yanni Gerges}, Joseph and Alicia D'Souza and Yanwen Wang and Ning Li and Hansen, {Brian J} and Stanislav Zakharkin and Matthew Smith and Christina Hayward and Whitson, {Bryan A} and Mohler, {Peter J.} and Janssen, {Paul M L} and Leo Zeef and Moinuddin Choudhury and Min Zi and Xue Cai and Sunil Logantha and Shu Nakao and Andrew Atkinson and Maria Petkova and Ursula Doris and Jonathan Ariyaratnam and Elizabeth Cartwright and Sam Griffiths-Jones and George Hart and Federov, {Vadim V.} and Delvac Oceandy and Halina Dobrzynski and Mark Boyett",

year = "2020",

month = jul,

day = "9",

doi = "10.1038/s41598-020-67790-0",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Springer Nature",

}

Yanni Gerges, J , D'Souza, A, Wang, Y, Li, N, Hansen, BJ, Zakharkin, S, Smith, M, Hayward, C, Whitson, BA, Mohler, PJ, Janssen, PML, Zeef, L, Choudhury, M, Zi, M, Cai, X, Logantha, S, Nakao, S, Atkinson, A, Petkova, M, Doris, U, Ariyaratnam, J, Cartwright, E , Griffiths-Jones, S, Hart, G, Federov, VV, Oceandy, D , Dobrzynski, H & Boyett, M 2020, 'Silencing miR-370-3p rescues funny current and sinus node function in heart failure', Scientific Reports, vol. 10, 11279. https://doi.org/10.1038/s41598-020-67790-0

TY - JOUR

T1 - Silencing miR-370-3p rescues funny current and sinus node function in heart failure

AU - Yanni Gerges, Joseph

AU - D'Souza, Alicia

AU - Wang, Yanwen

AU - Li, Ning

AU - Hansen, Brian J

AU - Zakharkin, Stanislav

AU - Smith, Matthew

AU - Hayward, Christina

AU - Whitson, Bryan A

AU - Mohler, Peter J.

AU - Janssen, Paul M L

AU - Zeef, Leo

AU - Choudhury, Moinuddin

AU - Zi, Min

AU - Cai, Xue

AU - Logantha, Sunil

AU - Nakao, Shu

AU - Atkinson, Andrew

AU - Petkova, Maria

AU - Doris, Ursula

AU - Ariyaratnam, Jonathan

AU - Cartwright, Elizabeth

AU - Griffiths-Jones, Sam

AU - Hart, George

AU - Federov, Vadim V.

AU - Oceandy, Delvac

AU - Dobrzynski, Halina

AU - Boyett, Mark

PY - 2020/7/9

Y1 - 2020/7/9

N2 - Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.

AB - Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, If, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of If , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and If in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.

U2 - 10.1038/s41598-020-67790-0

DO - 10.1038/s41598-020-67790-0

M3 - Article

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 11279

ER -

Silencing miR-370-3p rescues funny current and sinus node function in heart failure

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