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Published on: June 15, 2018
MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological
Dandan Yang1, Xiaoping Wan1, Neill Schwieterman2
1The Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, Frick Center for Heart Failure and Arrhythmia (D.Y., X.W., O.C., E.K., P.J.M., I.D., J.-D.F.), The Ohio State University, Columbus, OH.
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 or miR1-1) 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 Ca2+ 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.
Insights
MicroRNA-1 (miR1) deficiency causes cardiac remodeling and heart dysfunction. Restoring miR1 levels partially improved heart function but did not eliminate arrhythmia susceptibility.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- MicroRNA Therapeutics
Background:
- MicroRNA-1 (miR1) is crucial for heart development and function.
- Reduced miR1 expression is linked to heart diseases like atrial fibrillation and myocardial infarction.
- The role of miR1 deficiency as a cause of cardiac remodeling is unclear.
Purpose of the Study:
- To investigate the etiological role of miR1 deficiency in cardiac remodeling.
- To explore the molecular mechanisms underlying miR1-deficiency-induced cardiac dysfunction.
- To assess the therapeutic potential of miR1 restoration in a mouse model.
Main Methods:
- Generated 75% miR1-knockdown (75%KD) mice by crossbreeding miR1-1 and miR1-2 knockout lines.
- Assessed cardiac function using ECG, patch clamping, and optical mapping.
- Analyzed molecular changes via transcriptomic and proteomic assays.
- Administered miR1 mimics intravenously to evaluate therapeutic effects.
Main Results:
- 75%KD hearts showed reduced ejection fraction, prolonged QRS/QT intervals, and increased arrhythmia susceptibility.
- 75%KD cardiomyocytes exhibited altered action potentials, impaired excitation-contraction coupling, and dysregulated ion currents (reduced Na+, K+; elevated Ca2+).
- Transcriptomic and proteomic analyses revealed disrupted cardiac muscle contraction and ion channel regulation, with enrichment of smooth muscle contraction genes.
- miR1 mimic treatment partially improved cardiac function but did not resolve arrhythmia issues.
Conclusions:
- miR1 deficiency is a primary etiological factor in cardiac remodeling by disrupting heart regulatory homeostasis.
- Restoring miR1 levels offers potential therapeutic benefits for cardiovascular diseases.
- Maintaining stable miR1 expression is critical for effective microRNA-based cardiovascular therapies.
