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



Yanni, Joseph, D'Souza, Alicia, Wang, Yanwen, Li, Ning, Hansen, Brian J, Zakharkin, Stanislav O, Smith, Matthew, Hayward, Christina, Whitson, Bryan A, Mohler, Peter J
et al (show 18 more authors) (2020) Silencing miR-370-3p rescues funny current and sinus node function in heart failure. Scientific Reports, 10.

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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.

Item Type: Article
Uncontrolled Keywords: Cardiac hypertrophy, Heart failure
Depositing User: Symplectic Admin
Date Deposited: 22 Jul 2020 11:22
Last Modified: 19 Jan 2021 03:10
DOI: 10.1038/s41598-020-67790-0
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3094870

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