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

Overview

Journal Circ Arrhythm Electrophysiol

Specialty Cardiology & Vascular Diseases

Date 2023 Dec 21

PMID 38126205

Authors

Dandan Yang

Xiaoping Wan

Neill Schwieterman

Omer Cavus

Ege Kacira

Xianyao Xu

Kenneth R Laurita

Loren E Wold

Thomas J Hund

Peter J Mohler

Isabelle Deschenes

Ji-Dong Fu

Affiliations

Soon will be listed here.

Abstract

Background: MicroRNA-1 (miR1), encoded by the genes and , 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: or knockout mice were crossbred to produce 75%-miR1-knockdown (75%KD; or ) 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 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.

Citing Articles

microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.

Ismaeel A, Peck B, Montgomery M, Burke B, Goh J, Kang G bioRxiv. 2024; .

PMID: 39149347 PMC: 11326265. DOI: 10.1101/2024.08.09.607377.

References

Bhattacharya N, Ghosh S, Sept D, Cooper J . Binding of myotrophin/V-1 to actin-capping protein: implications for how capping protein binds to the filament barbed end. J Biol Chem. 2006; 281(41):31021-30. PMC: 2277501. DOI: 10.1074/jbc.M606278200. View

Tian X, Yong S, Wan X, Wu L, Chung M, Tchou P . Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. Cardiovasc Res. 2004; 61(2):256-67. PMC: 1579709. DOI: 10.1016/j.cardiores.2003.11.007. View

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

Patel R, West J, Jiang Y, Fogarty E, Grimson A . Robust partitioning of microRNA targets from downstream regulatory changes. Nucleic Acids Res. 2020; 48(17):9724-9746. PMC: 7515711. DOI: 10.1093/nar/gkaa687. View

Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov J . Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011; 27(12):1739-40. PMC: 3106198. DOI: 10.1093/bioinformatics/btr260. View

Li M, Chen X, Chen L, Chen K, Zhou J, Song J . MiR-1-3p that correlates with left ventricular function of HCM can serve as a potential target and differentiate HCM from DCM. J Transl Med. 2018; 16(1):161. PMC: 5994246. DOI: 10.1186/s12967-018-1534-3. View

Cohn J, Ferrari R, Sharpe N . Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000; 35(3):569-82. DOI: 10.1016/s0735-1097(99)00630-0. View

Bektik E, Dennis A, Prasanna P, Madabhushi A, Fu J . Single cell qPCR reveals that additional HAND2 and microRNA-1 facilitate the early reprogramming progress of seven-factor-induced human myocytes. PLoS One. 2017; 12(8):e0183000. PMC: 5552090. DOI: 10.1371/journal.pone.0183000. View

Tsao C, Aday A, Almarzooq Z, Alonso A, Beaton A, Bittencourt M . Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022; 145(8):e153-e639. DOI: 10.1161/CIR.0000000000001052. View

10.

Xu H, Ding Y, Shen Y, Xue A, Xu H, Luo C . MicroRNA- 1 represses Cx43 expression in viral myocarditis. Mol Cell Biochem. 2011; 362(1-2):141-8. DOI: 10.1007/s11010-011-1136-3. View

11.

Heidersbach A, Saxby C, Carver-Moore K, Huang Y, Ang Y, de Jong P . microRNA-1 regulates sarcomere formation and suppresses smooth muscle gene expression in the mammalian heart. Elife. 2013; 2:e01323. PMC: 3833424. DOI: 10.7554/eLife.01323. View

12.

Pinchi E, Frati P, Aromatario M, Cipolloni L, Fabbri M, La Russa R . miR-1, miR-499 and miR-208 are sensitive markers to diagnose sudden death due to early acute myocardial infarction. J Cell Mol Med. 2019; 23(9):6005-6016. PMC: 6714215. DOI: 10.1111/jcmm.14463. View

13.

Johnston A, Collins A, Goode B . High-speed depolymerization at actin filament ends jointly catalysed by Twinfilin and Srv2/CAP. Nat Cell Biol. 2015; 17(11):1504-11. PMC: 4808055. DOI: 10.1038/ncb3252. View

14.

Wei Y, Peng S, Wu M, Sachidanandam R, Tu Z, Zhang S . Multifaceted roles of miR-1s in repressing the fetal gene program in the heart. Cell Res. 2014; 24(3):278-92. PMC: 3945888. DOI: 10.1038/cr.2014.12. View

15.

Yang D, Wan X, Dennis A, Bektik E, Wang Z, Costa M . MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel. Circulation. 2021; 143(16):1597-1613. PMC: 8132313. DOI: 10.1161/CIRCULATIONAHA.120.050098. View

16.

Moseley J, Okada K, Balcer H, Kovar D, Pollard T, Goode B . Twinfilin is an actin-filament-severing protein and promotes rapid turnover of actin structures in vivo. J Cell Sci. 2006; 119(Pt 8):1547-57. DOI: 10.1242/jcs.02860. View

17.

Azevedo P, Polegato B, Minicucci M, Paiva S, Zornoff L . Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment. Arq Bras Cardiol. 2015; 106(1):62-9. PMC: 4728597. DOI: 10.5935/abc.20160005. View

18.

Terentyev D, Belevych A, Terentyeva R, Martin M, Malana G, Kuhn D . miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res. 2009; 104(4):514-21. PMC: 4394868. DOI: 10.1161/CIRCRESAHA.108.181651. View

19.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

20.

De Waard M, Pragnell M, Campbell K . Ca2+ channel regulation by a conserved beta subunit domain. Neuron. 1994; 13(2):495-503. DOI: 10.1016/0896-6273(94)90363-8. View