Abstract 12787: Microrna Administration Attenuates the Contraction Deterioration of Microrna-1 Deficient Heart But Not the Susceptibility of Arrhythmia

Abstract

Introduction: Aged people are much more likely to suffer arrhythmias or develop heart failure. MicroRNA-1 (miR1), encode by two distinct genes in the mammalian genome, is an evolutionarily conserved, striated muscle-enriched microRNA with a critical role in regulating cardiac physiology. Full knockout of miR1 in mice causes postnatal lethal. Interestingly, miR1 expression was significantly decreased to the level of 12.5±4.0% in the heart of 18-month aged animals, in comparison with that in young mice (age 3-4 months). Aims: We hypothesize that miR1 deficiency is one of the major etiologies in diseased and/or aged hearts and study the therapeutic effect of miR1 administration. Methods and Results: We generated miR1-75% knockdown (75%KD) mice and confirmed that miR1 expression was 4-5 fold lower in 75%KD hearts than in WT hearts. Echocardiogram showed that 75%KD mice demonstrated impaired cardiac contractile function, evidenced by decreased ejection fraction, and fraction shortening. Surface ECG recording showed that 75%KD mice had significantly lower heart rates, shorter PR interval, prolonged QRS interval as well as premature ventricular contractions. Consistently, optical mapping of ex vivo hearts revealed that 75%KD hearts had slower ventricular conduction velocity. Whole transcriptome RNA-sequencing and Proteomic assays demonstrated cardiac electrical and metabolic remodeling in miR1-deficient hearts. Compared to WT cells, 75%KD ventricular cardiomyocytes showed more hyperpolarized RMPs with prolonged APD; the sarcomere shortening was significantly decreased at a 5Hz fast pacing rate. Structurally, 75%KD myocytes had disrupted mitochondria with a shorter length of sarcomeres. We delivered miR into the animals through intravenous tail vein injection and found that 12-week miR1 administration could significantly attenuate the decrease of ejection fraction of 75%KD hearts, however, miR1-treated hearts had significantly higher inducibility of arrhythmia than control-RNA treated hearts. Conclusions: MicroRNA-1 deficiency causes cardiac electrical and metabolic remodeling. Restoring miR1 prevents the contraction deterioration of miR1-deficient hearts but increases the risk of arrhythmia.