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- Title
Silencing miR-370-3p rescues funny current and sinus node function in heart failure.
- Authors
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.; Janssen, Paul M. L.; Zeef, Leo; Choudhury, Moinuddin; Zi, Min; Cai, Xue; Logantha, Sunil Jit R. J.; Nakao, Shu; Atkinson, Andrew; Petkova, Maria; Doris, Ursula
- 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.
- Subjects
HEART failure; PACEMAKER cells; MICRORNA; DOWNREGULATION; SINOATRIAL node; INTRAPERITONEAL injections
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-67790-0