Key result
Intravenous miR1 mimics restore cardiac contractility and electrophysiology in miR1-knockdown mice.
Why the study?
It remained uncertain whether miR1 deficiency acts as a primary etiological factor of cardiac remodeling.
Does administration of miR1 mimics improve cardiac contractility and electrophysiological homeostasis in miR1-deficient mice?
Does administration of miR1 mimics improve cardiac contractility and electrophysiological homeostasis in miR1-deficient mice?
Answers are grounded in this paper and cite their sources.
MicroRNA-1 deficiency is a primary etiological factor in cardiac remodeling and electrophysiological dysfunction, and while miR1 mimics can rescue contractility, they may not fully reverse arrhythmia susceptibility.
BACKGROUND: MicroRNA-1 (miR1), encoded by the genes miR1-1 and miR1-2 , is the most abundant microRNA in the heart and plays a critical role in heart development and physiology. Dysregulation of miR1 has been associated with various heart diseases, where a significant reduction (>75%) in miR1 expression has been observed in patient hearts with atrial fibrillation or acute myocardial infarction. However, it remains uncertain whether miR1-deficiency acts as a primary etiological factor of cardiac remodeling. METHODS: miR1-1 or miR1-2 knockout mice were crossbred to produce 75%-miR1-knockdown (75%KD; miR1-1 +/− :miR1-2 −/− or miR1-1 −/− :miR1-2 +/− ) mice. Cardiac pathology of 75%KD cardiomyocytes/hearts was investigated by ECG, patch clamping, optical mapping, transcriptomic, and proteomic assays. RESULTS: In adult 75%KD hearts, the overall miR1 expression was reduced to ≈25% of the normal wild-type level. These adult 75%KD hearts displayed decreased ejection fraction and fractional shortening, prolonged QRS and QT intervals, and high susceptibility to arrhythmias. Adult 75%KD cardiomyocytes exhibited prolonged action potentials with impaired repolarization and excitation-contraction coupling. Comparatively, 75%KD cardiomyocytes showcased reduced Na + current and transient outward potassium current, coupled with elevated L-type Ca 2+ current, as opposed to wild-type cells. RNA sequencing and proteomics assays indicated negative regulation of cardiac muscle contraction and ion channel activities, along with a positive enrichment of smooth muscle contraction genes in 75%KD cardiomyocytes/hearts. miR1 deficiency led to dysregulation of a wide gene network, with miR1’s RNA interference–direct targets influencing many indirectly regulated genes. Furthermore, after 6 weeks of bi-weekly intravenous tail-vein injection of miR1 mimics, the ejection fraction and fractional shortening of 75%KD hearts showed significant improvement but remained susceptible to arrhythmias. CONCLUSIONS: miR1 deficiency acts as a primary etiological factor in inducing cardiac remodeling via disrupting heart regulatory homeostasis. Achieving stable and appropriate microRNA expression levels in the heart is critical for effective microRNA-based therapy in cardiovascular diseases.
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Yang et al. (2023) studied Cardiac remodeling and arrhythmias. miR1 mimics vs. Wild-type mice / baseline was evaluated on Cardiac pathology (ejection fraction, fractional shortening, electrophysiology). In 75%-miR1-knockdown mice, miR1 deficiency disrupted cardiac contractility and electrophysiology, which was significantly improved by 6 weeks of bi-weekly intravenous miR1 mimics.
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