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

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. Heart failure is a major health problem affecting ~ 26 million people worldwide and is one of the leading causes of hospitalisation in USA and Europe, resulting in over 1 million admissions/year as a primary diagnosis 1. Heart failure patients often have a relatively fast heart rate (> 70 beats/min) 2,3. β-blocker and ivabradine treatment received by heart failure patients lowers the heart rate 4,5 , which may or may not be the mechanism underlying the protective effects of these medications 4. Nevertheless, and paradoxically, bradyarrhythmias (excessively slow heart rates and rhythms) account for up to half of the deaths of end-stage heart failure patients 6-8. In the human and animal models, there is dysfunction of the pacemaker of the heart, the sinus node, in heart failure: there is a decrease in the intrinsic heart rate (the heart rate set by the sinus node in the absence of autonomic nerve activity) and an increase in the corrected sinus node recovery time (a frequently used measure of the functioning of the sinus node) 9-13. The dysfunction of the sinus node in heart failure has been attributed to fibrosis 14 and also remodelling of ion channels and corresponding ionic currents underlying the functioning of the sinus node 10,11,15,16. In particular, it has been attributed to a downregulation of the important pacemaker ion channel, HCN4, and the corresponding funny current, I f 11,15 ; however, the cause of the remodelling is not known.

RyR2 and Calcium Release in Heart Failure

“…The authors suggested that conjoint upregulation of RyR3 and calsequestrin 2 might however inhibit Ca 2+ release resulting in slow automaticity. More recently, the same group (Yanni et al, 2020) reported that pressure overload-induced HF in mice did not change SAN mRNA for various components of the "Ca 2+ clock, " including RyR2, SERCA, calsequestrin, and NCX. This is consistent with a study in isolated SAN cells from rabbit HF model of pressure and volume overload, which concluded that SAN Ca 2+ cycling properties are conserved despite bradycardic effects (Verkerk et al, 2015).…”

Arrhythmogenic Remodeling in the Failing Heart

“…In the sinus node, evidence suggests dysfunction and downregulation of I f in HF [9,10,162,163] which may cause bradyarrhythmia in certain situations. In contrast, in the ventricle, I f is upregulated (Figure 9) [164][165][166] which was attributed to enhanced mRNA and protein expressions of HNC2 and HCN4 channels in the failing human ventricle [167].…”

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

“…Finally, extensive linkage and genome-wide associated studies [18,[45][46][47][48][49][50][51][52], posttranscriptional analyses, and next-generation sequencing [49,[53][54][55][56][57][58][59][60][61][62] on animal and human tissues and cells, included pluripotent stem cells [63,64], shed light on the ontology of the genes regulated during CCS development and physiology, as well as on their fine-tune silencing provided by specific microRNAs (e.g., miR-1 and miR-128a). Each component of the CCS is, hence, the developmental embryology result of unique hierarchical transcriptional networks, with a prominent orchestrating or ruling role by T-box transcription factors, as previously summarized by Munshi in 2012 [65].…”