MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis

Details

• Personal Author:
  Cavus O ; Deschênes I ; Fu J-D ; Hund TJ ; Kacira E ; Laurita KR ; Mohler PJ ; Schwieterman N ; Wan X ; Wold LE ; Xu X ; Yang D
• Description:
  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 approx. = 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. [Description provided by NIOSH]
• Subjects:
  Cardiovascular System Occupational Health Safety
• Keywords:
  Author Keywords: Arrhythmia Cardiac Function Cardiovascular Health Circulatory System Gene Expression Heart Contractility Heart Rate MicroRNAs Pathogenesis Ribonucleic Acids RNA Ventricle Remodeling

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• ISSN:
  1941-3084
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 3 ; OSHA Region 5 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  17
• Issue:
  1
• NIOSHTIC Number:
  nn:20069314
• Citation:
  Circ Arrhythm Electrophysiol 2024 Jan; 17(1):e012150
• Contact Point Address:
  Ji-Dong Fu, PhD, Department of Physiology and Cell Biology, Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Graves Hall 5071, 333 W 10th Ave, Columbus, OH 43210
• Email:
  jidong.fu@osumc.edu
• Federal Fiscal Year:
  2024
• Performing Organization:
  Ohio State University
• Peer Reviewed:
  True
• Start Date:
  20200701
• Source Full Name:
  Circulation: Arrhythmia and Electrophysiology
• End Date:
  20210630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c63f7775c9055728f41068bf1291c6cd661ee354e3f872472f278c4d69aabb9936d4e4716ed0719c62a84d0e12f6241359aae5c9f8a65683562632630846df22
• Download URL:
  https://stacks.cdc.gov/view/cdc/207814/cdc_207814_DS1.pdf
• File Type:
  [PDF - 4.48 MB ]