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 -