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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 |
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Article number | 11279 |
Journal | Scientific Reports |
Volume | 10 |
DOIs | |
Publication status | Published - 9 Jul 2020 |
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The Role of Plasma Membrane Calcium ATPase 4 (PMCA4) in Modulating Plasmodium Infection and Malaria Severity.
Oceandy, D. (PI) & Couper, K. (CoI)
1/10/17 → 31/07/20
Project: Research