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MicroRNA-1 Deficiency is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis
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1 2024
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Source: Circ Arrhythm Electrophysiol. 17(1):e012150
[PDF-2.67 MB]
Details:
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Alternative Title:Circ Arrhythm Electrophysiol
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Personal Author:
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Description:Background:
MicroRNA-1 (miR1), encoded by the genes miR1-1 and miR1-2, is the most abundant miR 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 were investigated by echocardiogram, 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 wildtype (WT) level. These adult 75%KD heart displayed decreased ejection fraction (EF) and fractional shortening (FS), 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 INa (Na+ current) and Ito (transient outward potassium current), coupled with elevated ICa,L (L-type Ca2+ current), as opposed to WT 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 RNAi direct targets influencing many indirectly-regulated genes. Furthermore, after 6 weeks of bi-weekly intravenous tail-vein injection of miR1 mimics, the EF and FS 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 miR expression levels in the heart is critical for effective miR-based therapy in cardiovascular diseases.
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Pubmed ID:38126205
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Pubmed Central ID:PMC10842700
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Volume:17
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Issue:1
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