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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.
Circulation. Arrhythmia and Electrophysiology
|December 21, 2023
Summary
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.
