Silencing miR-370-3p rescues funny current and sinus node function in heart failure
Joseph Yanni, Alicia D’Souza, Yanwen Wang, Ning Li, Brian J. Hansen, Stanislav O. Zakharkin, Matthew Smith, Christina Hayward, Bryan A. Whitson, Peter J. Mohler, Paul M.L. Janssen, Leo Zeef, Moinuddin Choudhury, Min Zi, Xue Cai, Sunil Jit R. J. Logantha, Shu Nakao, Andrew Atkinson, Mária Peťková, Ursula Doris, Jonathan Ariyaratnam, Elizabeth J. Cartwright, Sam Griffiths‐Jones, George Hart, Vadim V. Fedorov, Delvac Oceandy, Halina Dobrzynski, Mark R. Boyett
Abstract
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, I f , in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I f , 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 I f 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.