{"doi":"10.1161/circep.123.012150","title":"MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis","abstract":"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 ≈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 2+ 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.","journal":"Circulation Arrhythmia and Electrophysiology","year":2023,"id":329114,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1051734,"name":"Xiaoping Wan","orcid":"0009-0006-0417-3437","position":1,"is_corresponding":false},{"id":789946,"name":"Neill Schwieterman","orcid":"0000-0002-9736-8703","position":2,"is_corresponding":false},{"id":724648,"name":"Omer Cavus","orcid":"0000-0002-2930-3975","position":3,"is_corresponding":false},{"id":1052355,"name":"Ege Kacira","orcid":null,"position":4,"is_corresponding":false},{"id":701034,"name":"Xianyao Xu","orcid":"0000-0001-7834-4880","position":5,"is_corresponding":false},{"id":728353,"name":"Kenneth R. Laurita","orcid":"0000-0002-6341-9656","position":6,"is_corresponding":false},{"id":401659,"name":"Loren E. Wold","orcid":"0000-0001-8155-0204","position":7,"is_corresponding":false},{"id":317225,"name":"Thomas J. Hund","orcid":"0000-0002-9957-7306","position":8,"is_corresponding":false},{"id":350645,"name":"Peter J. Mohler","orcid":"0000-0002-7977-8717","position":9,"is_corresponding":false},{"id":478428,"name":"Isabelle Deschênes","orcid":"0000-0002-1812-7267","position":10,"is_corresponding":false},{"id":40463,"name":"Ji‐Dong Fu","orcid":"0000-0003-2797-5193","position":11,"is_corresponding":false},{"id":758472,"name":"Dandan Yang","orcid":"0000-0002-7696-4434","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:09:01.509601Z","pmid":"38126205","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}