|
1
|
Balan AI, Scridon A. MicroRNAs in atrial fibrillation - have we discovered the Holy Grail or opened a Pandora's box? Front Pharmacol 2025; 16:1535621. [PMID: 40012622 PMCID: PMC11861496 DOI: 10.3389/fphar.2025.1535621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/24/2025] [Indexed: 02/28/2025] Open
Abstract
Atrial fibrillation (AF) causes a heavy socio-economic burden on healthcare systems around the globe. Identification of new preventive, diagnostic, and treatment methods is imperative. In recent years, special attention has been paid to microRNAs (miRNAs) as potential regulators of AF pathogenesis. Through post-transcriptional regulation of genes, miRNAs have been shown to play crucial roles in AF-related structural and electrical atrial remodeling. Altered expression of different miRNAs has been related to proarrhythmic changes in the duration of action potentials and atrial fibrosis. In clinical studies, miRNA changes have been associated with AF, whereas in experimental studies miRNA manipulation has emerged as a potential therapeutic approach. It would appear that, with the advent of miRNAs, we may have found the Holy Grail, and that efficient and personalized AF therapy may be one step away. Yet, the clinical relevance of miRNA evaluation and manipulation remains questionable. Studies have identified numerous miRNAs associated with AF, but none of them have shown sufficient specificity for AF. MicroRNAs are not gene-specific but regulate the expression of a myriad of genes. Cardiac and non-cardiac off-target effects may thus occur following miRNA manipulation. A Pandora's box might thus have opened with the advent of these sophisticated molecules. In this paper, we provide a critical analysis of the clinical and experimental, epidemiological and mechanistic data linking miRNAs to AF, we discuss the most promising miRNA therapeutic approaches, we emphasize a number of questions that remain to be answered, and we identify hotspots for future research.
Collapse
Affiliation(s)
| | - Alina Scridon
- Physiology Department and Center for Advanced Medical and Pharmaceutical Research, Pharmacy, Science and Technology “George Emil Palade” of Târgu Mureș, University of Medicine, Târgu Mures, Romania
| |
Collapse
|
|
2
|
Vardas EP, Oikonomou E, Vardas PE, Tousoulis D. MicroRNAs as Prognostic Biomarkers for Atrial Fibrillation Recurrence After Catheter Ablation: Current Evidence and Future Directions. Biomedicines 2024; 13:32. [PMID: 39857616 PMCID: PMC11762821 DOI: 10.3390/biomedicines13010032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with significant morbidity and mortality. Even though catheter ablation has emerged as an available and effective treatment for AF, recurrence remains a significant challenge. This review presents the existing evidence on the prognostic role of microRNAs (miRNAs) in the prediction of AF recurrence after catheter ablation. We examined studies investigating the association between miRNA expression and post-ablation AF recurrence. Multiple miRNAs have been highlighted as potential biomarkers, which are involved in pathophysiological processes such as atrial remodeling, fibrosis, and inflammation. Despite some promising results, there has been significant heterogeneity across the studies. In this review, we demonstrate the potential miRNAs that can be routinely used as biomarkers of AF recurrence, and we identify areas that require further research to validate their clinical utility.
Collapse
Affiliation(s)
- Emmanouil P. Vardas
- 1st Cardiology Department, General Hospital of Athens “Hippokration”, University of Athens Medical School, 11528 Athens, Greece;
- Department of Cardiology, General Hospital of Athens “G. Gennimatas”, 11527 Athens, Greece
| | - Evangelos Oikonomou
- 3rd Cardiology Department, Sotiria Regional Hospital for Chest Diseases, University of Athens Medical School, 11527 Athens, Greece
| | - Panos E. Vardas
- Biomedical Research Foundation Academy of Athens, Heart Sector, Hygeia Hospitals Group, Attica, 15123 Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Department, General Hospital of Athens “Hippokration”, University of Athens Medical School, 11528 Athens, Greece;
| |
Collapse
|
|
3
|
Chen X, Zhang Y, Meng H, Chen G, Ma Y, Li J, Liu S, Liang Z, Xie Y, Liu Y, Guo H, Wang Y, Shan Z. Identification of miR-1 and miR-499 in chronic atrial fibrillation by bioinformatics analysis and experimental validation. Front Cardiovasc Med 2024; 11:1400643. [PMID: 39221422 PMCID: PMC11361948 DOI: 10.3389/fcvm.2024.1400643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Background Atrial fibrillation (AF) is one of the most prevalent arrhythmias and is characterized by a high risk of heart failure and embolic stroke, yet its underlying mechanism is unclear. The primary goal of this study was to establish a miRNA-mRNA network and identify the miRNAs associated with chronic AF by bioinformatics and experimental validation. Methods The GSE79768 dataset was collected from the Gene Expression Omnibus(GEO) database to extract data from patients with or without persistent AF. Differentially expressed genes (DEGs) were identified in left atrial appendages (LAAs). The STRING platform was utilized for protein-protein interaction (PPI) network analysis. The target miRNAs for the top 20 hub genes were predicted by using the miRTarBase Web tool. The miRNA-mRNA network was established and visualized using Cytoscape software. The key miRNAs selected for verification in the animal experiment were confirmed by miRwalk Web tool. We used a classic animal model of rapid ventricular pacing for chronic AF. Two groups of animals were included in the experiment, namely, the ventricular pacing group (VP group), where ventricular pacing was maintained at 240-280 bpm for 2 weeks, and the control group was the sham-operated group (SO group). Finally, we performed reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to validate the expression of miR-1 and miR-499 in LAA tissues of the VP group and the SO group. Left atrial fibrosis and apoptosis were evaluated by Masson staining and caspase-3 activity assays, respectively. Results The networks showed 48 miRNAs in LAA tissues. MiR-1 and miR-499 were validated using an animal model of chronic AF. The expression level of miR-1 was increased, and miR-499 was decreased in VP group tissues compared to SO group tissues in LAAs (P < 0.05), which were correlated with left atrial fibrosis and apoptosis in AF. Conclusion This study provides a better understanding of the alterations in miRNA-1 and miR-499 in chronic AF from the perspective of the miRNA-mRNA network and corroborates findings through experimental validation. These findings may offer novel potential therapeutic targets for AF in the future.
Collapse
Affiliation(s)
- Xinpei Chen
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
- Department of Cardiac Arrhythmia, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Yu Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Beijing, China
| | - He Meng
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Guiying Chen
- Department of Pneumology, Tianjin Chest Hospital, Tianjin, China
| | - Yongjiang Ma
- Department of Cardiology, The Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Jian Li
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
| | - Saizhe Liu
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
| | - Zhuo Liang
- Department of Cardiology, Beijing Anzhen Hospital, Beijing, China
| | - Yinuo Xie
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
| | - Ying Liu
- Department of Cardiology, Beijing Jing Mei Group General Hospital, Beijing, China
| | - Hongyang Guo
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
| | - Yutang Wang
- Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Zhaoliang Shan
- Munich Medical Research School, Ludwig-Maximilians University Munich, Munich, Germany
| |
Collapse
|
|
4
|
Vardas EP, Theofilis P, Oikonomou E, Vardas PE, Tousoulis D. MicroRNAs in Atrial Fibrillation: Mechanisms, Vascular Implications, and Therapeutic Potential. Biomedicines 2024; 12:811. [PMID: 38672166 PMCID: PMC11048414 DOI: 10.3390/biomedicines12040811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/27/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Atrial fibrillation (AFib), the most prevalent arrhythmia in clinical practice, presents a growing global health concern, particularly with the aging population, as it is associated with devastating complications and an impaired quality of life. Its pathophysiology is multifactorial, including the pathways of fibrosis, inflammation, and oxidative stress. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as substantial contributors in AFib pathophysiology, by affecting those pathways. In this review, we explore the intricate relationship between miRNAs and the aforementioned aspects of AFib, shedding light on the molecular pathways as well as the potential diagnostic applications. Recent evidence also suggests a possible role of miRNA therapeutics in maintenance of sinus rhythm via the antagonism of miR-1 and miR-328, or the pharmacological upregulation of miR-27b and miR-223-3p. Unraveling the crosstalk between specific miRNA profiles and genetic predispositions may pave the way for personalized therapeutic approaches, setting the tone for precision medicine in atrial fibrillation.
Collapse
Affiliation(s)
- Emmanouil P. Vardas
- 1st Cardiology Department, General Hospital of Athens “Hippokration”, University of Athens Medical School, 11528 Athens, Greece; (E.P.V.); (P.T.)
- Department of Cardiology, General Hospital of Athens “G. Gennimatas”, 11527 Athens, Greece
| | - Panagiotis Theofilis
- 1st Cardiology Department, General Hospital of Athens “Hippokration”, University of Athens Medical School, 11528 Athens, Greece; (E.P.V.); (P.T.)
| | - Evangelos Oikonomou
- 3rd Cardiology Department, Sotiria Regional Hospital for Chest Diseases, University of Athens Medical School, 11527 Athens, Greece;
| | - Panos E. Vardas
- Biomedical Research Foundation Academy of Athens, Heart Sector, Hygeia Hospitals Group, Attica, 15123 Athens, Greece;
| | - Dimitris Tousoulis
- 1st Cardiology Department, General Hospital of Athens “Hippokration”, University of Athens Medical School, 11528 Athens, Greece; (E.P.V.); (P.T.)
| |
Collapse
|
|
5
|
Lozano-Velasco E, Inácio JM, Sousa I, Guimarães AR, Franco D, Moura G, Belo JA. miRNAs in Heart Development and Disease. Int J Mol Sci 2024; 25:1673. [PMID: 38338950 PMCID: PMC10855082 DOI: 10.3390/ijms25031673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/25/2024] [Accepted: 01/27/2024] [Indexed: 02/12/2024] Open
Abstract
Cardiovascular diseases (CVD) are a group of disorders that affect the heart and blood vessels. They include conditions such as myocardial infarction, coronary artery disease, heart failure, arrhythmia, and congenital heart defects. CVDs are the leading cause of death worldwide. Therefore, new medical interventions that aim to prevent, treat, or manage CVDs are of prime importance. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level and play important roles in various biological processes, including cardiac development, function, and disease. Moreover, miRNAs can also act as biomarkers and therapeutic targets. In order to identify and characterize miRNAs and their target genes, scientists take advantage of computational tools such as bioinformatic algorithms, which can also assist in analyzing miRNA expression profiles, functions, and interactions in different cardiac conditions. Indeed, the combination of miRNA research and bioinformatic algorithms has opened new avenues for understanding and treating CVDs. In this review, we summarize the current knowledge on the roles of miRNAs in cardiac development and CVDs, discuss the challenges and opportunities, and provide some examples of recent bioinformatics for miRNA research in cardiovascular biology and medicine.
Collapse
Affiliation(s)
- Estefania Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (E.L.-V.); (D.F.)
| | - José Manuel Inácio
- Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal;
| | - Inês Sousa
- Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine–iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal; (I.S.); (A.R.G.); (G.M.)
| | - Ana Rita Guimarães
- Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine–iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal; (I.S.); (A.R.G.); (G.M.)
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain; (E.L.-V.); (D.F.)
| | - Gabriela Moura
- Genome Medicine Lab, Department of Medical Sciences, Institute for Biomedicine–iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal; (I.S.); (A.R.G.); (G.M.)
| | - José António Belo
- Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal;
| |
Collapse
|
|
6
|
Yang D, Wan X, Schwieterman N, Cavus O, Kacira E, Xu X, Laurita KR, Wold LE, Hund TJ, Mohler PJ, Deschênes I, Fu JD. MicroRNA-1 Deficiency Is a Primary Etiological Factor Disrupting Cardiac Contractility and Electrophysiological Homeostasis. Circ Arrhythm Electrophysiol 2024; 17:e012150. [PMID: 38126205 PMCID: PMC10842700 DOI: 10.1161/circep.123.012150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023]
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 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.
Collapse
Affiliation(s)
- Dandan Yang
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| | - Xiaoping Wan
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| | - Neill Schwieterman
- The Dorothy M. Davis Heart and Lung Research Institute, Dept of Surgery, Division of Cardiac Surgery, The Ohio State University, Columbus
| | - Omer Cavus
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
- Pennsylvania State University, Heart and Vascular Institute, Hershey, PA
| | - Ege Kacira
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| | - Xianyao Xu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Depts of Internal Medicine & Biomedical Engineering, The Ohio State University, Columbus
| | - Kenneth R. Laurita
- Dept of Medicine, Heart and Vascular Research Center, The MetroHealth System, Case Western Reserve University, Cleveland, OH
| | - Loren E. Wold
- The Dorothy M. Davis Heart and Lung Research Institute, Dept of Surgery, Division of Cardiac Surgery, The Ohio State University, Columbus
| | - Thomas J. Hund
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Depts of Internal Medicine & Biomedical Engineering, The Ohio State University, Columbus
| | - Peter J. Mohler
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| | - Isabelle Deschênes
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| | - Ji-Dong Fu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Dept of Physiology and Cell Biology, The Ohio State University, Columbus
| |
Collapse
|
|
7
|
Lee J, Lee H, Sherbini AE, Baghaie L, Leroy F, Abdel-Qadir H, Szewczuk MR, El-Diasty M. Epigenetic MicroRNAs as Prognostic Markers of Postoperative Atrial Fibrillation: A Systematic Review. Curr Probl Cardiol 2024; 49:102106. [PMID: 37741599 DOI: 10.1016/j.cpcardiol.2023.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery, increasing the risk for adverse outcomes such as perioperative and long-term mortality, stroke, myocardial infarction, and other thromboembolic events. Epigenetic biomarkers show promise as prognostic tools for POAF. Epigenetic changes, such as DNA methylation, histone modification, and microRNAs (miRNA), can result in altered gene expression and the development of various pathological conditions. This systematic review aims to present the current literature on the association between various epigenetic markers and the development of POAF following cardiac surgery. Here, an electronic literature search was performed using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar to identify studies that reported the role of epigenetic markers in the development of POAF. Five of the 6 studies focused on miRNAs and their association with POAF. In POAF patients, the expression of miR-1 and miR-483-5p were upregulated in the right atrial appendage (RAA), while the levels of miR-133A, miR-208a, miR-23a, miR-26a, miR-29a, miR-29b, and miR-29c were decreased in the RAA and venous blood. One study examined cytosines followed by guanines (CpGs) as DNA methylation markers. Across all studies, 488 human subjects who had undergone cardiac surgery were investigated, and 195 subjects (39.9%) developed new-onset POAF. The current literature suggests that miRNAs may play a role in predicting the development of atrial fibrillation after cardiac surgery. However, more robust clinical data are required to justify their role in routine clinical practice.
Collapse
Affiliation(s)
- Junsu Lee
- Faculty of Health Sciences, Queen's University, Kingston, ON, Canada
| | - Hyunmin Lee
- Faculty of Health Sciences, Queen's University, Kingston, ON, Canada
| | - Adham El Sherbini
- Faculty of Health Sciences, Queen's University, Kingston, ON, Canada
| | - Leili Baghaie
- Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Fleur Leroy
- Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada; Faculté de Médecine, Maïeutique et Sciences de la Santé, Université de Strasbourg, Strasbourg, France
| | - Husam Abdel-Qadir
- Women's College Hospital, Peter Munk Cardiac Center, Toronto, ON, Canada
| | - Myron R Szewczuk
- Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Mohammad El-Diasty
- Department of Cardiac Surgery, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH.
| |
Collapse
|
|
8
|
Sharma AK, Singh S, Bhat M, Gill K, Zaid M, Kumar S, Shakya A, Tantray J, Jose D, Gupta R, Yangzom T, Sharma RK, Sahu SK, Rathore G, Chandolia P, Singh M, Mishra A, Raj S, Gupta A, Agarwal M, Kifayat S, Gupta A, Gupta P, Vashist A, Vaibhav P, Kathuria N, Yadav V, Singh RP, Garg A. New drug discovery of cardiac anti-arrhythmic drugs: insights in animal models. Sci Rep 2023; 13:16420. [PMID: 37775650 PMCID: PMC10541452 DOI: 10.1038/s41598-023-41942-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 09/04/2023] [Indexed: 10/01/2023] Open
Abstract
Cardiac rhythm regulated by micro-macroscopic structures of heart. Pacemaker abnormalities or disruptions in electrical conduction, lead to arrhythmic disorders may be benign, typical, threatening, ultimately fatal, occurs in clinical practice, patients on digitalis, anaesthesia or acute myocardial infarction. Both traditional and genetic animal models are: In-vitro: Isolated ventricular Myocytes, Guinea pig papillary muscles, Patch-Clamp Experiments, Porcine Atrial Myocytes, Guinea pig ventricular myocytes, Guinea pig papillary muscle: action potential and refractory period, Langendorff technique, Arrhythmia by acetylcholine or potassium. Acquired arrhythmia disorders: Transverse Aortic Constriction, Myocardial Ischemia, Complete Heart Block and AV Node Ablation, Chronic Tachypacing, Inflammation, Metabolic and Drug-Induced Arrhythmia. In-Vivo: Chemically induced arrhythmia: Aconitine antagonism, Digoxin-induced arrhythmia, Strophanthin/ouabain-induced arrhythmia, Adrenaline-induced arrhythmia, and Calcium-induced arrhythmia. Electrically induced arrhythmia: Ventricular fibrillation electrical threshold, Arrhythmia through programmed electrical stimulation, sudden coronary death in dogs, Exercise ventricular fibrillation. Genetic Arrhythmia: Channelopathies, Calcium Release Deficiency Syndrome, Long QT Syndrome, Short QT Syndrome, Brugada Syndrome. Genetic with Structural Heart Disease: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Atrial Fibrillation, Sick Sinus Syndrome, Atrioventricular Block, Preexcitation Syndrome. Arrhythmia in Pluripotent Stem Cell Cardiomyocytes. Conclusion: Both traditional and genetic, experimental models of cardiac arrhythmias' characteristics and significance help in development of new antiarrhythmic drugs.
Collapse
Affiliation(s)
- Ashish Kumar Sharma
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India.
| | - Shivam Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mehvish Bhat
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Kartik Gill
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mohammad Zaid
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Sachin Kumar
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anjali Shakya
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Junaid Tantray
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Divyamol Jose
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Rashmi Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Tsering Yangzom
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Rajesh Kumar Sharma
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | | | - Gulshan Rathore
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Priyanka Chandolia
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mithilesh Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anurag Mishra
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Shobhit Raj
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Archita Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Mohit Agarwal
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Sumaiya Kifayat
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Anamika Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Prashant Gupta
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Ankit Vashist
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Parth Vaibhav
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Nancy Kathuria
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Vipin Yadav
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Ravindra Pal Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan, 303121, India
| | - Arun Garg
- MVN University, Palwal, Haryana, India
| |
Collapse
|
|
9
|
Parent S, Vaka R, Risha Y, Ngo C, Kanda P, Nattel S, Khan S, Courtman D, Stewart DJ, Davis DR. Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy. JCI Insight 2023; 8:e163297. [PMID: 37384420 PMCID: PMC10481795 DOI: 10.1172/jci.insight.163297] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 06/28/2023] [Indexed: 07/01/2023] Open
Abstract
Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex-independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis were markedly attenuated by EV pretreatment, an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of EVs at the time of open-chest surgery shows prominent antiinflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent postoperative AF by reducing atrial inflammation and fibrosis.
Collapse
Affiliation(s)
- Sandrine Parent
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ramana Vaka
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Yousef Risha
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Clarissa Ngo
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
| | - Pushpinder Kanda
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Stanley Nattel
- Research Center and Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Saad Khan
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David Courtman
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Duncan J. Stewart
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Darryl R. Davis
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, and
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
10
|
Desantis V, Potenza MA, Sgarra L, Nacci C, Scaringella A, Cicco S, Solimando AG, Vacca A, Montagnani M. microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation. Int J Mol Sci 2023; 24:5307. [PMID: 36982382 PMCID: PMC10049145 DOI: 10.3390/ijms24065307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/07/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
The pathophysiology of atrial fibrillation (AF) may involve atrial fibrosis/remodeling and dysfunctional endothelial activities. Despite the currently available treatment approaches, the progression of AF, its recurrence rate, and the high mortality risk of related complications underlay the need for more advanced prognostic and therapeutic strategies. There is increasing attention on the molecular mechanisms controlling AF onset and progression points to the complex cell to cell interplay that triggers fibroblasts, immune cells and myofibroblasts, enhancing atrial fibrosis. In this scenario, endothelial cell dysfunction (ED) might play an unexpected but significant role. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level. In the cardiovascular compartment, both free circulating and exosomal miRNAs entail the control of plaque formation, lipid metabolism, inflammation and angiogenesis, cardiomyocyte growth and contractility, and even the maintenance of cardiac rhythm. Abnormal miRNAs levels may indicate the activation state of circulating cells, and thus represent a specific read-out of cardiac tissue changes. Although several unresolved questions still limit their clinical use, the ease of accessibility in biofluids and their prognostic and diagnostic properties make them novel and attractive biomarker candidates in AF. This article summarizes the most recent features of AF associated with miRNAs and relates them to potentially underlying mechanisms.
Collapse
Affiliation(s)
- Vanessa Desantis
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Maria Assunta Potenza
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Luca Sgarra
- General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy
| | - Carmela Nacci
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Antonietta Scaringella
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Sebastiano Cicco
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Monica Montagnani
- Department of Precision and Regenerative Medicine and Ionian Area, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| |
Collapse
|
|
11
|
Donniacuo M, De Angelis A, Telesca M, Bellocchio G, Riemma MA, Paolisso P, Scisciola L, Cianflone E, Torella D, Castaldo G, Capuano A, Urbanek K, Berrino L, Rossi F, Cappetta D. Atrial fibrillation: Epigenetic aspects and role of sodium-glucose cotransporter 2 inhibitors. Pharmacol Res 2023; 188:106591. [PMID: 36502999 DOI: 10.1016/j.phrs.2022.106591] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022]
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with substantial morbidity and mortality. Pathophysiological aspects consist in the activation of pro-fibrotic signaling and Ca2+ handling abnormalities at atrial level. Structural and electrical remodeling creates a substrate for AF by triggering conduction abnormalities and cardiac arrhythmias. The care of AF patients focuses predominantly on anticoagulation, symptoms control and the management of risk factors and comorbidities. The goal of AF therapy points to restore sinus rhythm, re-establish atrioventricular synchrony and improve atrial contribution to the stroke volume. New layer of information to better comprehend AF pathophysiology, and identify targets for novel pharmacological interventions consists of the epigenetic phenomena including, among others, DNA methylation, histone modifications and noncoding RNAs. Moreover, the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in diabetic and non-diabetic patients at cardiovascular risk as well as emerging evidence on the ability of SGLT2i to modify epigenetic signature in cardiovascular diseases provide a solid background to investigate a possible role of this drug class in the onset and progression of AF. In this review, following a summary of pathophysiology and management, epigenetic mechanisms in AF and the potential of sodium-glucose SGLT2i in AF patients are discussed.
Collapse
Affiliation(s)
- M Donniacuo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - A De Angelis
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - M Telesca
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - G Bellocchio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - M A Riemma
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - P Paolisso
- Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium; Department of Advanced Biomedical Sciences, University of Naples "Federico II", Via A. Pansini 5, 80131 Naples, Italy
| | - L Scisciola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - E Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, Viale Europa, 88100 Catanzaro, Italy
| | - D Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, Viale Europa, 88100 Catanzaro, Italy
| | - G Castaldo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via A. Pansini 5, 80131 Naples, Italy; CEINGE-Advanced, Via G. Salvatore 486, 80131 Naples, Italy
| | - A Capuano
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - K Urbanek
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via A. Pansini 5, 80131 Naples, Italy; CEINGE-Advanced, Via G. Salvatore 486, 80131 Naples, Italy.
| | - L Berrino
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - F Rossi
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - D Cappetta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| |
Collapse
|
|
12
|
Fan W, Sun X, Yang C, Wan J, Luo H, Liao B. Pacemaker activity and ion channels in the sinoatrial node cells: MicroRNAs and arrhythmia. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:151-167. [PMID: 36450332 DOI: 10.1016/j.pbiomolbio.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 11/13/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
The primary pacemaking activity of the heart is determined by a spontaneous action potential (AP) within sinoatrial node (SAN) cells. This unique AP generation relies on two mechanisms: membrane clocks and calcium clocks. Nonhomologous arrhythmias are caused by several functional and structural changes in the myocardium. MicroRNAs (miRNAs) are essential regulators of gene expression in cardiomyocytes. These miRNAs play a vital role in regulating the stability of cardiac conduction and in the remodeling process that leads to arrhythmias. Although it remains unclear how miRNAs regulate the expression and function of ion channels in the heart, these regulatory mechanisms may support the development of emerging therapies. This study discusses the spread and generation of AP in the SAN as well as the regulation of miRNAs and individual ion channels. Arrhythmogenicity studies on ion channels will provide a research basis for miRNA modulation as a new therapeutic target.
Collapse
Affiliation(s)
- Wei Fan
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Xuemei Sun
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Chao Yang
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China
| | - Juyi Wan
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| | - Hongli Luo
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| | - Bin Liao
- Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan Province, 646000, China.
| |
Collapse
|
|
13
|
Lu Y, Zhao N, Du Y. Comprehensive bioinformatics analysis reveals common potential mechanisms, progression markers, and immune cells of coronary virus disease 2019 and atrial fibrillation. Front Cardiovasc Med 2022; 9:1027026. [PMID: 36352845 PMCID: PMC9637541 DOI: 10.3389/fcvm.2022.1027026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/07/2022] [Indexed: 12/01/2023] Open
Abstract
OBJECTIVES Atrial fibrillation (AF) is the most common arrhythmia in coronary virus disease 2019 (COVID-19) patients, especially in severe patients. A history of AF can exacerbate COVID-19 symptoms. COVID-19 Patients with new-onset AF have prolonged hospital stays and increased death risk. However, the mechanisms and targets of the interaction between COVID-19 and AF have not been elucidated. MATERIALS AND METHODS We used a series of bioinformatics analyses to understand biological pathways, protein-protein interaction (PPI) networks, gene regulatory networks (GRNs), and protein-chemical interactions between COVID-19 and AF and constructed an AF-related gene signature to assess COVID-19 severity and prognosis. RESULTS We found folate and one-carbon metabolism, calcium regulation, and TFG-β signaling pathway as potential mechanisms linking COVID-19 and AF, which may be involved in alterations in neutrophil metabolism, inflammation, and endothelial cell function. We identified hug genes and found that NF-κb, hsa-miR-1-3p, hsa-miR-124-3p, valproic acid, and quercetin may be key regulatory molecules. We constructed a 3-gene signature consisting of ARG1, GIMAP7, and RFX2 models for the assessment of COVID-19 severity and prognosis, and found that they are associated with neutrophils, T cells, and hematopoietic stem cells, respectively. CONCLUSION Our study reveals a dysregulation of metabolism, inflammation, and immunity between COVID-19 and AF, and identified several therapeutic targets and progression markers. We hope that the results will reveal important insights into the complex interactions between COVID-19 and AF that will drive novel drug development and help in severity assessment.
Collapse
Affiliation(s)
- Yang Lu
- Department of Cardiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Research Center of Ion Channelopathy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Tongji Medical College, Union Hospital, Institute of Cardiology, Huazhong University of Science and Technology, Wuhan, China
- Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ning Zhao
- Department of Cardiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Research Center of Ion Channelopathy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Tongji Medical College, Union Hospital, Institute of Cardiology, Huazhong University of Science and Technology, Wuhan, China
- Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yimei Du
- Department of Cardiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Research Center of Ion Channelopathy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Tongji Medical College, Union Hospital, Institute of Cardiology, Huazhong University of Science and Technology, Wuhan, China
- Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
14
|
Benito B, García-Elías A, Ois Á, Tajes M, Vallès E, Ble M, Yáñez Bisbe L, Giralt-Steinhauer E, Rodríguez-Campello A, Cladellas Capdevila M, Martí-Almor J, Roquer J, Cuadrado-Godia E. Plasma levels of miRNA-1-3p are associated with subclinical atrial fibrillation in patients with cryptogenic stroke. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2022; 75:717-726. [PMID: 35067470 DOI: 10.1016/j.rec.2021.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 11/30/2021] [Indexed: 06/14/2023]
Abstract
INTRODUCTION AND OBJECTIVES Identifying biomarkers of subclinical atrial fibrillation (AF) is of most interest in patients with cryptogenic stroke (CrS). We sought to evaluate the circulating microRNA (miRNA) profile of patients with CrS and AF compared with those in persistent sinus rhythm. METHODS Among 64 consecutive patients with CrS under continuous monitoring by a predischarge insertable monitor, 18 patients (9 with AF and 9 in persistent sinus rhythm) were selected for high-throughput determination of 754 miRNAs. Nine patients with concomitant stroke and AF were also screened to improve the yield of miRNA selection. Differentially expressed miRNAs were replicated in an independent cohort (n=46). Biological markers were stratified by the median and included in logistic regression analyses to evaluate their association with AF at 6 and 12 months. RESULTS Eight miRNAs were differentially expressed between patients with and without AF. In the replication cohort, miR-1-3p, a gene regulator involved in cardiac arrhythmogenesis, was the only miRNA to remain significantly higher in patients with CrS and AF vs those in sinus rhythm and showed a modest association with AF burden. High (= above the median) miR-1-3p plasma values, together with a low left atrial ejection fraction, were independently associated with the presence of AF at 6 and 12 months. CONCLUSIONS In this cohort, plasma levels of miR-1-3p were elevated in CrS patients with subsequent AF. Our results preliminarily suggest that miR-1-3p could be a novel biomarker that, together with clinical parameters, could help identify patients with CrS and a high risk of occult AF.
Collapse
Affiliation(s)
- Begoña Benito
- Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Spain.
| | - Anna García-Elías
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Research Center, Montreal Heart Institute, Montreal, Canada
| | - Ángel Ois
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Neurología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Marta Tajes
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain
| | - Ermengol Vallès
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Mireia Ble
- Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | | | - Eva Giralt-Steinhauer
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Ana Rodríguez-Campello
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Mercè Cladellas Capdevila
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Julio Martí-Almor
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Jaume Roquer
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| | - Elisa Cuadrado-Godia
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Parc de Salut Mar, Barcelona, Spain; Servicio de Cardiología, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
| |
Collapse
|
|
15
|
Abstract
Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide, accounting for 10% to 15% of all deaths. Although most arrhythmias are due to acquired heart disease, inherited channelopathies and cardiomyopathies disproportionately affect children and young adults. Arrhythmogenesis is complex, involving anatomic structure, ion channels and regulatory proteins, and the interplay between cells in the conduction system, cardiomyocytes, fibroblasts, and the immune system. Animal models of arrhythmia are powerful tools for studying not only molecular and cellular mechanism of arrhythmogenesis but also more complex mechanisms at the whole heart level, and for testing therapeutic interventions. This review summarizes basic and clinical arrhythmia mechanisms followed by an in-depth review of published animal models of genetic and acquired arrhythmia disorders.
Collapse
Affiliation(s)
- Daniel J Blackwell
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Jeffrey Schmeckpeper
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Bjorn C Knollmann
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| |
Collapse
|
|
16
|
Yang D, Deschênes I, Fu JD. Multilayer control of cardiac electrophysiology by microRNAs. J Mol Cell Cardiol 2022; 166:107-115. [PMID: 35247375 PMCID: PMC9035102 DOI: 10.1016/j.yjmcc.2022.02.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/22/2022] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
The electrophysiological properties of the heart include cardiac automaticity, excitation (i.e., depolarization and repolarization of action potential) of individual cardiomyocytes, and highly coordinated electrical propagation through the whole heart. An abnormality in any of these properties can cause arrhythmias. MicroRNAs (miRs) have been recognized as essential regulators of gene expression through the conventional RNA interference (RNAi) mechanism and are involved in a variety of biological events. Recent evidence has demonstrated that miRs regulate the electrophysiology of the heart through fine regulation by the conventional RNAi mechanism of the expression of ion channels, transporters, intracellular Ca2+-handling proteins, and other relevant factors. Recently, a direct interaction between miRs and ion channels has also been reported in the heart, revealing a biophysical modulation by miRs of cardiac electrophysiology. These advanced discoveries suggest that miR controls cardiac electrophysiology through two distinct mechanisms: immediate action through biophysical modulation and long-term conventional RNAi regulation. Here, we review the recent research progress and summarize the current understanding of how miR manipulates the function of ion channels to maintain the homeostasis of cardiac electrophysiology.
Collapse
Affiliation(s)
- Dandan Yang
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA
| | - Isabelle Deschênes
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA
| | - Ji-Dong Fu
- The Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, Department of Physiology and Cell Biology, The Ohio State University, 333 W. 10(th) Avenue, Columbus, OH 43210, USA.
| |
Collapse
|
|
17
|
Benito B, García-Elías A, Ois Á, Tajes M, Vallès E, Ble M, Yáñez Bisbe L, Giralt-Steinhauer E, Rodríguez-Campello A, Cladellas Capdevila M, Martí-Almor J, Roquer J, Cuadrado-Godia E. La concentración plasmática de microARN-1-3p se asocia con fibrilación auricular subclínica en los pacientes con ictus criptogénico. Rev Esp Cardiol 2022. [DOI: 10.1016/j.recesp.2021.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
18
|
Li D, Nie J, Han Y, Ni L. Epigenetic Mechanism and Therapeutic Implications of Atrial Fibrillation. Front Cardiovasc Med 2022; 8:763824. [PMID: 35127848 PMCID: PMC8815458 DOI: 10.3389/fcvm.2021.763824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/08/2021] [Indexed: 12/28/2022] Open
Abstract
Atrial fibrillation (AF) is the most common arrhythmia attacking 1. 5–2.0% of general population worldwide. It has a significant impact on morbidity and mortality globally and its prevalence increases exponentially with age. Therapies like catheter ablation or conventional antiarrhythmic drugs have not provided effective solution to the recurrence for AF over the past decades. Over 100 genetic loci have been discovered to be associated with AF by Genome-wide association studies (GWAS) but none has led to a therapy. Recently potential involvement of epigenetics (DNA methylation, histone modification, and non-coding RNAs) in the initiation and maintenance of AF has partly emerged as proof-of-concept in the mechanism and management of AF. Here we reviewed the epigenetic features involved in AF pathophysiology and provided an update of their implications in AF therapy.
Collapse
|
|
19
|
Samolovac S, Hinkel R. Locked Nucleic Acid AntimiR Therapy for the Heart. Methods Mol Biol 2022; 2573:159-169. [PMID: 36040593 DOI: 10.1007/978-1-0716-2707-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Coronary heart disease is one of the leading causes of death in industrialized nations. Even though revascularization strategies improved the outcome of patients after acute myocardial infarction, about 30% of patients develop chronic heart failure. Ischemic heart disease and heart failure are characterized by an adverse remodeling of the heart, featuring cardiomyocyte hypertrophy, increased fibrosis, and capillary rarefaction. Therefore, novel therapeutic approaches for the treatment of heart failure, such as reducing ischemia/reperfusion injury, fibrosis, or hypertrophy, are needed. Here microRNAs (miRNAs) come into play. For heart failure, cardiac stress and several cardiovascular diseases, individual miRNAs, and whole miRNA clusters have been implicated as disease relevant and dysregulated. miRNAs are short non-coding RNA molecules of about 22 nucleotides, and their inhibitors are 8-15 nucleotides long plus a sugar-ring (LNA, locked nucleid acid) or cholesterol ending (AntagomiR). Modulation of miRNAs might serve as therapeutic targets through miRNA knockdown or overexpression via miRNA mimics. Due to their pleiotropic mode of action and the presence of individual miRNAs in a variety of tissues and cells, a local, target region-oriented application is important to achieve therapeutic effects and at the same time reducing adverse effects in other off-target organs and tissues. Due to their small size, the miRNA inhibitors are able to pass endothelial barrier at both arterial and venous sides of the bloodstream vessels. For these reasons, the gold standard administration route of miRNA modulators for therapeutic approaches of the left ventricle is the anterograde application into one or both coronary arteries via an over-the-wire (OTW) balloon. In this chapter we provide a comprehensive description of the anterograde application procedure in a large animal model such as pig. Of a particular note, this methodology is a standard procedure in catheter laboratories, a key characteristic that allows therapeutic translation from large animals to patients.
Collapse
Affiliation(s)
| | - Rabea Hinkel
- Deutsches Primatenzentrum GmbH, Göttingen, Germany.
| |
Collapse
|
|
20
|
Koniari I, Artopoulou E, Velissaris D, Ainslie M, Mplani V, Karavasili G, Kounis N, Tsigkas G. Biomarkers in the clinical management of patients with atrial fibrillation and heart failure. J Geriatr Cardiol 2021; 18:908-951. [PMID: 34908928 PMCID: PMC8648548 DOI: 10.11909/j.issn.1671-5411.2021.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Atrial fibrillation (AF) and heart failure (HF) are two cardiovascular diseases with an increasing prevalence worldwide. These conditions share common pathophysiologiesand frequently co-exit. In fact, the occurrence of either condition can 'cause' the development of the other, creating a new patient group that demands different management strategies to that if they occur in isolation. Regardless of the temproral association of the two conditions, their presence is linked with adverse cardiovascular outcomes, increased rate of hospitalizations, and increased economic burden on healthcare systems. The use of low-cost, easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF. Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information. These will then guide patient centred therapeutic management. The current biomarkers that offer potential for guiding therapy, focus on the physiological pathways of miRNA, myocardial stretch and injury, oxidative stress, inflammation, fibrosis, coagulation and renal impairment. Each of these has different utility in current clinincal practice.
Collapse
Affiliation(s)
- Ioanna Koniari
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Mark Ainslie
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
- Division of Cardiovascular Sciences, University of Manchester
| | - Virginia Mplani
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Georgia Karavasili
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| |
Collapse
|
|
21
|
Zhang L, Wang X, Huang C. A narrative review of non-coding RNAs in atrial fibrillation: potential therapeutic targets and molecular mechanisms. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1486. [PMID: 34734038 PMCID: PMC8506732 DOI: 10.21037/atm-21-4483] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 11/11/2022]
Abstract
Objective This review summarizes the advances in the study of ncRNAs and atrial remodeling mechanisms to explore potential therapeutic targets and strategies for AF. Background Atrial fibrillation (AF) is one of the most common arrhythmias, and its morbidity and mortality rates are gradually increasing. Non-coding ribonucleic acid RNAs (ncRNAs) are transcribed from the genome and do not have the ability to be translated into proteins. A growing body of evidence has shown ncRNAs are extensively involved in the pathophysiological processes underlying AF. However, the precise molecular mechanisms of these associations have not been fully elucidated. Atrial remodeling plays a key role in the occurrence and development of AF, and includes electrical remodeling, structural remodeling, and autonomic nerve remodeling. Research has shown that ncRNA expression is altered in the plasma and tissues of AF patients that mediate cardiac excitation and arrhythmia, and is closely related to atrial remodeling. Methods Literatures about ncRNAs and atrial fibrillation were extensively reviewed to discuss and analyze. Conclusions The biology of ncRNAs represents a relatively new field of research and is still in an emerging stage. Recent studies have laid a foundation for understanding the molecular mechanisms of AF, future studies aimed at identifying how ncRNAs act on atrial fibrillation to provide potentially promising therapeutic targets for the treatment of atrial fibrillation.
Collapse
Affiliation(s)
- Lan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Congxin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| |
Collapse
|
|
22
|
Chaulin AM, Duplyakov DV. Microrna: the role in the pathophysiology of atrial fibrillation and potential use as a biomarker. BULLETIN OF SIBERIAN MEDICINE 2021. [DOI: 10.20538/1682-0363-2021-3-203-212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
Abstract
The aim of the study was to analyze medical literature on the role of microRNA in the pathophysiology of atrial fibrillation and the possibilities of using microRNAs as biomarkers.The analysis of modern medical literature was carried out using the PubMed – NCBI database.Atrial fibrillation (AF) is a common and serious cardiovascular disease. The pathophysiological mechanisms underlying the development of atrial fibrillation are not entirely clear. In addition, there are no optimal biomarkers for early detection and assessment of the prognosis for patients with atrial fibrillation. Recently, the attention of researchers has been directed to the molecules of microRNA. There is a lot of evidence that they are involved in the pathogenesis of neurological, oncological, and cardiovascular diseases. This review examines the role of microRNAs in the pathophysiology of atrial fibrillation. The possibility of using microRNA as a biomarker for the diagnosis and prediction of atrial fibrillation is also discussed.MicroRNAs play a crucial role in the pathophysiology of atrial fibrillation, regulating the mechanisms of atrial remodeling, such as electrical remodeling, structural remodeling, remodeling of the autonomic nervous system, and impaired regulation of calcium levels. The stability of microRNAs and the possibility to study them in various biological fluids and tissues, including blood, make these molecules a promising diagnostic biomarker for various cardiovascular diseases. The presented data clearly indicate that AF is associated with changes in the expression level of various microRNAs, which can be quantified using a polymerase chain reaction. Further research is required to assess the role of microRNAs as biomarkers for atrial fibrillation, in particular to establish precise reference limits.
Collapse
|
|
23
|
Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases. HEARTS 2021. [DOI: 10.3390/hearts2030026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, our current understanding of the functional roles of non-coding RNAs have progressively increased. microRNAs represent the most studied type of small ncRNAs and it has been demonstrated that miRNAs play essential roles in multiple biological contexts, including normal development and diseases. In this review, we provide a comprehensive analysis of the functional contribution of non-coding RNAs, primarily microRNAs, to the normal configuration of the cardiac action potential, as well as their association to distinct types of arrhythmogenic cardiac diseases.
Collapse
|
|
24
|
Zhang XD, Thai PN, Lieu DK, Chiamvimonvat N. Model Systems for Addressing Mechanism of Arrhythmogenesis in Cardiac Repair. Curr Cardiol Rep 2021; 23:72. [PMID: 34050853 PMCID: PMC8164614 DOI: 10.1007/s11886-021-01498-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 11/09/2022]
Abstract
PURPOSE OF REVIEW Cardiac cell-based therapy represents a promising approach for cardiac repair. However, one of the main challenges is cardiac arrhythmias associated with stem cell transplantation. The current review summarizes the recent progress in model systems for addressing mechanisms of arrhythmogenesis in cardiac repair. RECENT FINDINGS Animal models have been extensively developed for mechanistic studies of cardiac arrhythmogenesis. Advances in human induced pluripotent stem cells (hiPSCs), patient-specific disease models, tissue engineering, and gene editing have greatly enhanced our ability to probe the mechanistic bases of cardiac arrhythmias. Additionally, recent development in multiscale computational studies and machine learning provides yet another powerful tool to quantitatively decipher the mechanisms of cardiac arrhythmias. Advancing efforts towards the integrations of experimental and computational studies are critical to gain insights into novel mitigation strategies for cardiac arrhythmias in cell-based therapy.
Collapse
Affiliation(s)
- Xiao-Dong Zhang
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA 95616 USA
- Department of Veterans Affairs, Veterans Affairs Northern California Health Care System, Mather, CA 95655 USA
| | - Phung N. Thai
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA 95616 USA
- Department of Veterans Affairs, Veterans Affairs Northern California Health Care System, Mather, CA 95655 USA
| | - Deborah K. Lieu
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA 95616 USA
| | - Nipavan Chiamvimonvat
- Division of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, CA 95616 USA
- Department of Veterans Affairs, Veterans Affairs Northern California Health Care System, Mather, CA 95655 USA
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA 95616 USA
| |
Collapse
|
|
25
|
Oltra E. Epigenetics of muscle disorders. MEDICAL EPIGENETICS 2021:279-308. [DOI: 10.1016/b978-0-12-823928-5.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
26
|
Ravelli F, Masè M. MicroRNAs: New contributors to mechano-electric coupling and atrial fibrillation. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2020; 159:146-156. [PMID: 33011190 DOI: 10.1016/j.pbiomolbio.2020.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 09/17/2020] [Accepted: 09/27/2020] [Indexed: 12/29/2022]
Abstract
Atrial fibrillation (AF) is a multifactorial disease, which often occurs in the presence of underlying cardiac abnormalities and is supported by electrophysiological and structural alterations, generally referred to as atrial remodeling. Abnormal substrates are commonly encountered in various conditions that predispose to AF, such as hypertension, heart failure, obesity, and sleep apnea, in which atrial stretch plays a key mechanistic role. Emerging evidence suggests a role for microRNAs (small non-coding RNAs) in the pathogenesis of AF, where they can act as post-transcriptional regulators of the genes involved in atrial remodeling. This review summarizes the experimental and clinical evidence that supports the role of microRNAs in the modulation of atrial electrical and structural remodeling with a focus on overload-induced atrial alterations, and discusses the potential contribution of microRNAs to mechano-electrical coupling and AF.
Collapse
Affiliation(s)
- Flavia Ravelli
- Laboratory of Biophysics and Biosignals, University of Trento, Trento, Italy.
| | - Michela Masè
- Institute of Mountain Emergency Medicine, Eurac Research, Bolzano, Italy; Healthcare Research and Innovation Program, IRCS-HTA, Bruno Kessler Foundation, Trento, Italy
| |
Collapse
|
|
27
|
Du J, Li Z, Wang X, Li J, Liu D, Wang X, Wei J, Ma S, Zhang Y, Hou Y. Long noncoding RNA TCONS-00106987 promotes atrial electrical remodelling during atrial fibrillation by sponging miR-26 to regulate KCNJ2. J Cell Mol Med 2020; 24:12777-12788. [PMID: 32954646 PMCID: PMC7687017 DOI: 10.1111/jcmm.15869] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/06/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been suggested to play indispensable roles in multiple heart diseases. However, the correlations between lncRNAs and atrial fibrillation (AF) are unclear. In this study, we performed comprehensive lncRNA profiling via high-throughput RNA sequencing analysis using non-AF and AF rabbit models. Based on a series of filtering pipelines and bioinformatics analyses, TCONS-00106987 was selected for further research. TCONS-00106987 levels were increased in the atria during AF. Moreover, the atrial effective refractory period was shortened and the AF inducibility was increased in vivo in response to lentiviral-mediated up-regulation of TCONS-00106987. TCONS-00106987 repression resulted in the opposite effects. Further studies indicated that TCONS-00106987 expression was positively correlated with the expression of the protein-coding gene KCNJ2. Luciferase reporter assays and whole-cell patch-clamp recording confirmed that TCONS-00106987 promoted electrical remodelling via endogenous competition with microRNA-26 (miR-26) to induce transcription of its target gene KCNJ2, thereby increasing inward-rectifier K+ current (IK1 ). In conclusion, our study reveals a pathogenic lncRNA-miRNA regulatory network specific to atrial electrical remodelling that offers potential therapeutic targets for AF.
Collapse
Affiliation(s)
- Juanjuan Du
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhan Li
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiao Wang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianhua Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Donglu Liu
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ximin Wang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jinqiu Wei
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shenzhou Ma
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yujiao Zhang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yinglong Hou
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| |
Collapse
|
|
28
|
Hosen MR, Goody PR, Zietzer A, Nickenig G, Jansen F. MicroRNAs As Master Regulators of Atherosclerosis: From Pathogenesis to Novel Therapeutic Options. Antioxid Redox Signal 2020; 33:621-644. [PMID: 32408755 DOI: 10.1089/ars.2020.8107] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Significance: Cardiovascular disease (CVD) remains the major cause of morbidity and mortality worldwide. Accumulating evidence indicates that atherosclerosis and its sequelae, coronary artery disease, contribute to the majority of cardiovascular deaths. Atherosclerosis is a chronic inflammatory disease of the arteries in which atherosclerotic plaques form within the vessel wall. Epidemiological studies have identified various risk factors for atherosclerosis, such as diabetes, hyperlipidemia, smoking, genetic predisposition, and sedentary lifestyle. Recent Advances: Through the advancement of genetic manipulation techniques and their use in cardiovascular biology, it was shown that small RNAs, especially microRNAs (miRNAs), are dynamic regulators of disease pathogenesis. They are considered to be central during the regulation of gene expression through numerous mechanisms and provide a means to develop biomarkers and therapeutic tools for the diagnosis and therapy of atherosclerosis. Circulating miRNAs encapsulated within membrane-surrounded vesicles, which originate from diverse subcellular compartments, are now emerging as novel regulators of intercellular communication. The miRNAs, in both freely circulating and vesicle-bound forms, represent a valuable tool for diagnosing and monitoring CVD, recently termed as "liquid biopsy." Critical Issues: However, despite the recent advancements in miRNA-based diagnostics and therapeutics, understanding how miRNAs can regulate atherosclerosis is still crucial to achieving an effective intervention and reducing the disease burden. Future Directions: We provide a landscape of the current developmental progression of RNA therapeutics as a holistic approach for treating CVD in different animal models and clinical trials. Future interrogations are warranted for the development of miRNA-based therapeutics to overcome challenges for the treatment of the disease.
Collapse
Affiliation(s)
- Mohammed Rabiul Hosen
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Philip Roger Goody
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Andreas Zietzer
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Georg Nickenig
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Felix Jansen
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| |
Collapse
|
|
29
|
Genetics and Epigenetics of Atrial Fibrillation. Int J Mol Sci 2020; 21:ijms21165717. [PMID: 32784971 PMCID: PMC7460853 DOI: 10.3390/ijms21165717] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks
Collapse
|
|
30
|
Bektik E, Cowan DB, Wang DZ. Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System. Int J Mol Sci 2020; 21:ijms21155424. [PMID: 32751460 PMCID: PMC7432754 DOI: 10.3390/ijms21155424] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/19/2022] Open
Abstract
Atrial fibrillation (AF) is a type of sustained arrhythmia in humans often characterized by devastating alterations to the cardiac conduction system as well as the structure of the atria. AF can lead to decreased cardiac function, heart failure, and other complications. Long non-coding RNAs (lncRNAs) have been shown to play important roles in the cardiovascular system, including AF; however, a large group of lncRNAs is not conserved between mouse and human. Furthermore, AF has complex networks showing variations in mechanisms in different species, making it challenging to utilize conventional animal models to investigate the functional roles and potential therapeutic benefits of lncRNAs for AF. Fortunately, pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) offer a reliable platform to study lncRNA functions in AF because of certain electrophysiological and molecular similarities with native human CMs. In this review, we first summarize the broad aspects of lncRNAs in various heart disease settings, then focus on their potential roles in AF development and pathophysiology. We also discuss current uses of PSCs in AF research and describe how these studies could be developed into novel therapeutics for AF and other cardiovascular diseases.
Collapse
Affiliation(s)
- Emre Bektik
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood, Boston, MA 02115, USA; (E.B.); (D.B.C.)
| | - Douglas B. Cowan
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood, Boston, MA 02115, USA; (E.B.); (D.B.C.)
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood, Boston, MA 02115, USA; (E.B.); (D.B.C.)
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Correspondence:
| |
Collapse
|
|
31
|
Franco D, Aranega A, Dominguez JN. Non-coding RNAs and Atrial Fibrillation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:311-325. [PMID: 32285421 DOI: 10.1007/978-981-15-1671-9_19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Atrial fibrillation is the most frequent type of cardiac arrhythmia in humans, with an estimate incidence of 1-2% in the general population, rising up to 8-10% in the elderly. Cardiovascular risk factors such as diabetes, obesity, hypertension and hyperthyroidism can increase the occurrence of AF. The onset of AF triggers additional AF episodes, leading to structural and electrical remodeling of the diseased heart. Understanding the molecular bases of atrial fibrillation have greatly advance over the last decade demonstrating a pivotal role of distinct ion channels in AF pathophysiology. A new scenario has opened on the understanding of the molecular mechanisms underlying AF, with the discovery of non-coding RNAs and their wide implication in multiple disease states, including cardiac arrhythmogenic pathologies. microRNAs are small non-coding RNAs of 22-24 nucleotides that are capable of regulating gene expression by interacting with the mRNA transcript 3'UTRs and promoting mRNA degradation and/or protein translation blockage. Long non-coding RNAs are a more diverse group of non-coding RNAs, providing transcriptional and post-transcriptional roles and subclassified according to their functional properties. In this chapter we summarized current state-of-the-art knowledge on the functional of microRNAs and long non-coding RNAs as well as their cross-talk regulatory mechanisms in atrial fibrillation.
Collapse
Affiliation(s)
- Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain.
| | - Amelia Aranega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Jorge N Dominguez
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| |
Collapse
|
|
32
|
The Therapeutic Potential of MicroRNAs in Atrial Fibrillation. Mediators Inflamm 2020; 2020:3053520. [PMID: 32256190 PMCID: PMC7091547 DOI: 10.1155/2020/3053520] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
One of the most globally prevalent supraventricular arrhythmias is atrial fibrillation (AF). Knowledge of the structures and functions of messenger RNA (mRNA) has recently increased. It is no longer viewed as solely an intermediate molecule between DNA and proteins but has come to be seen as a dynamic and modifiable gene regulator. This new perspective on mRNA has led to rising interest in it and its presence in research into new therapeutic schemes. This paper, therefore, focuses on microRNAs (miRNAs), which are small noncoding RNAs that regulate posttranscriptional gene expression and play a vital role in the physiology and normative development of cardiovascular systems. This means they play an equally vital role in the development and progression of cardiovascular diseases. In recent years, multiple studies have pinpointed particular miRNA expression profiles as being associated with varying histological features of AF. These studies have been carried out in both animal models and AF patients. The emergence of miRNAs as biomarkers and their therapeutic potential in AF patients will be discussed in the body of this paper.
Collapse
|
|
33
|
Abstract
RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.
Collapse
Affiliation(s)
- Cheng-Kai Huang
- From the Institute of Molecular and Translational Therapeutic Strategies (C.-K.H., S.K.-K., T.T.), Hannover Medical School, Germany
| | - Sabine Kafert-Kasting
- From the Institute of Molecular and Translational Therapeutic Strategies (C.-K.H., S.K.-K., T.T.), Hannover Medical School, Germany
| | - Thomas Thum
- From the Institute of Molecular and Translational Therapeutic Strategies (C.-K.H., S.K.-K., T.T.), Hannover Medical School, Germany
- REBIRTH Center of Translational Regenerative Medicine (T.T.), Hannover Medical School, Germany
| |
Collapse
|
|
34
|
Kura B, Kalocayova B, Devaux Y, Bartekova M. Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection. Int J Mol Sci 2020; 21:ijms21030700. [PMID: 31973111 PMCID: PMC7037063 DOI: 10.3390/ijms21030700] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/10/2020] [Accepted: 01/17/2020] [Indexed: 02/07/2023] Open
Abstract
The interest in non-coding RNAs, which started more than a decade ago, has still not weakened. A wealth of experimental and clinical studies has suggested the potential of non-coding RNAs, especially the short-sized microRNAs (miRs), to be used as the new generation of therapeutic targets and biomarkers of cardiovascular disease, an ever-growing public health issue in the modern world. Among the hundreds of miRs characterized so far, microRNA-1 (miR-1) and microRNA-21 (miR-21) have received some attention and have been associated with cardiac injury and cardioprotection. In this review article, we summarize the current knowledge of the function of these two miRs in the heart, their association with cardiac injury, and their potential cardioprotective roles and biomarker value. While this field has already been extensively studied, much remains to be done before research findings can be translated into clinical application for patient’s benefit.
Collapse
Affiliation(s)
- Branislav Kura
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (B.K.); (B.K.)
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81372 Bratislava, Slovakia
| | - Barbora Kalocayova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (B.K.); (B.K.)
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg;
| | - Monika Bartekova
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (B.K.); (B.K.)
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 81372 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-2-3229-5427
| |
Collapse
|
|
35
|
Šustr F, Stárek Z, Souček M, Novák J. Non-coding RNAs and Cardiac Arrhythmias. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:287-300. [PMID: 32285419 DOI: 10.1007/978-981-15-1671-9_17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
Cardiac arrhythmias represent wide and heterogenic group of disturbances in the cardiac rhythm. Pathophysiology of individual arrhythmias is highly complex and dysfunction in ion channels/currents involved in generation or spreading of action potential is usually documented. Non-coding RNAs (ncRNAs) represent highly variable group of molecules regulating the heart expression program, including regulation of the expression of individual ion channels and intercellular connection proteins, e.g. connexins.Within this chapter, we will describe basic electrophysiological properties of the myocardium. We will focus on action potential generation and spreading in pacemaker and non-pacemaker cells, including description of individual ion channels (natrium, potassium and calcium) and their ncRNA-mediated regulation. Most of the studies have so far focused on microRNAs, thus, their regulatory function will be described into greater detail. Clinical consequences of altered ncRNA regulatory function will also be described together with potential future directions of the research in the field.
Collapse
Affiliation(s)
- Filip Šustr
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zdeněk Stárek
- First Department of Internal Medicine and Cardioangiology of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Miroslav Souček
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jan Novák
- Second Department of Internal Medicine of St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
- CEITEC - Central European Institute for Technology, Masaryk University, Brno, Czech Republic.
| |
Collapse
|
|
36
|
Shen NN, Zhang C, Li Z, Kong LC, Wang XH, Gu ZC, Wang JL. MicroRNA expression signatures of atrial fibrillation: The critical systematic review and bioinformatics analysis. Exp Biol Med (Maywood) 2019; 245:42-53. [PMID: 31766887 DOI: 10.1177/1535370219890303] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Association between microRNA (miRNA) expression signatures and atrial fibrillation has been evaluated with inconsistent findings in different studies. This study aims to identify miRNAs that actually play vital role in pathophysiological process of atrial fibrillation and explore miRNA-targeted genes and the involved pathways. Relevant studies were retrieved from the electronic databases of Embase, Medline, and Cochrane Library to determine the miRNA expression profiles between atrial fibrillation subjects and non-atrial fibrillation controls. Robustness of results was assessed using sensitivity analysis. Subgroup analyses were performed based on species, miRNA detection method, sample source, and ethnicity. Quality assessment of studies was independently conducted according to QUADAS-2. Bioinformatics analysis was applied to explore the potential genes and pathways associated with atrial fibrillation, which were targeted by differentially expressed miRNAs. Form of pooled results was shown as log10 odds ratios (logORs) with 95% confidence intervals (CI), and random-effects model was used. In total, 40 articles involving 283 differentially expressed miRNAs were reported. And 51 significantly dysregulated miRNAs were identified in consistent direction, with 22 upregulated and 29 downregulated. Among above-mentioned miRNAs, miR-223-3p (logOR 6.473; P < 0.001) was the most upregulated, while miR-1-5p (logOR 7.290; P < 0.001) was the most downregulated. Subgroup analysis confirmed 53 significantly dysregulated miRNAs (21 upregulated and 32 downregulated) in cardiac tissue, with miRNA-1-5p and miRNA-223-3p being the most upregulated and downregulated miRNAs, respectively. Additionally, miR-328 and miR-1-5p were highly blood-specific, and miR-133 was animal-specific. In the detection method sub-groups, miRNA-29b and miRNA-223-3p were differentially expressed consistently. Four miRNAs, including miRNA-223-3p, miRNA-21, miRNA-328, and miRNA-1-5p, were consistently dysregulated in both Asian and non-Asian. Results of sensitivity analysis showed that 47 out of 51 (92.16%) miRNAs were dysregulated consistently. Totally, 51 consistently dysregulated miRNAs associated with atrial fibrillation were confirmed in this study. Five important miRNAs, including miR-29b, miR-328, miR-1-5p, miR-21, and miR-223-3p may act as potential biomarkers for atrial fibrillation. Impact statement Atrial fibrillation (AF) is considered as the most common arrhythmia, and it subsequently causes serious complications including thrombosis and heart failure that increase the social burden. The definite mechanisms underlying AF pathogenesis remain complicated and unclear. Many studies attempted to discover the transcriptomic changes using microarray technologies, and the present studies for this hot topic have assessed individual miRNAs profiles for AF. However, results of different articles are controversial and not each reported miRNA is actually associated with the pathogenesis of AF. The present systematic review and meta-analysis identified that 51 consistently dysregulated miRNAs were associated with AF. Of these miRNAs, five miRNAs (miRNA-1-5p, miRNA-328, miRNA-29b, miRNA-21, and miRNA-223-3p) may act as novel biomarkers for AF. The findings could offer a better description of the biological characteristics of miRNAs, meanwhile might serve as new target for the intervention and monitoring AF in future studies.
Collapse
Affiliation(s)
- Nan-Nan Shen
- Department of Pharmacy, Affiliated Hospital of Shaoxing University, Shao Xing 312000, China.,State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chi Zhang
- State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zheng Li
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ling-Cong Kong
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xin-Hua Wang
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zhi-Chun Gu
- State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jia-Liang Wang
- Department of Pharmacy, Affiliated Hospital of Shaoxing University, Shao Xing 312000, China
| |
Collapse
|
|
37
|
Masè M, Grasso M, Avogaro L, Nicolussi Giacomaz M, D'Amato E, Tessarolo F, Graffigna A, Denti MA, Ravelli F. Upregulation of miR-133b and miR-328 in Patients With Atrial Dilatation: Implications for Stretch-Induced Atrial Fibrillation. Front Physiol 2019; 10:1133. [PMID: 31551809 PMCID: PMC6748158 DOI: 10.3389/fphys.2019.01133] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022] Open
Abstract
Atrial stretch and dilatation are common features of many clinical conditions predisposing to atrial fibrillation (AF). MicroRNAs (miRs) are emerging as potential molecular determinants of AF, but their relationship with atrial dilatation (AD) is poorly understood. The present study was designed to assess the specific miR expression profiles associated with AD in human atrial tissue. The expressions of a preselected panel of miRs, previously described as playing a role in cardiac disease, were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in atrial tissue samples from 30 cardiac surgery patients, who were characterized by different grades of AD and arrhythmic profiles. Our results showed that AD per se was associated with significant up-regulation of miR-328-3p and miR-133b (p < 0.05) with respect to controls, with a fold-change of 1.53 and 1.74, respectively. In a multivariate model including AD and AF as independent variables, miR-328-3p expression was mainly associated with AD grade (p < 0.05), while miR-133b was related to both AD (p < 0.005) and AF (p < 0.05), the two factors exerting opposite modulation effects. The presence of AF was associated with significant (p < 0.05) up-regulation of the expression level of miR-1-3p, miR-21-5p, miR-29a-3p, miR-208b-3p, and miR-590-5p. These results showed the existence of specific alterations of miR expression associated with AD, which may pave the way to future experimental studies to test the involvement of post-transcriptional mechanisms in the stretch-induced formation of a pro-arrhythmic substrate.
Collapse
Affiliation(s)
- Michela Masè
- Laboratory of Biophysics and Biosignals, University of Trento, Trento, Italy.,Healthcare Research and Innovation Program, Bruno Kessler Foundation, Trento, Italy
| | - Margherita Grasso
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Laura Avogaro
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | | | - Elvira D'Amato
- Laboratory of Biophysics and Biosignals, University of Trento, Trento, Italy
| | - Francesco Tessarolo
- Healthcare Research and Innovation Program, Bruno Kessler Foundation, Trento, Italy
| | - Angelo Graffigna
- Division of Cardiac Surgery, Santa Chiara Hospital, Trento, Italy
| | - Michela Alessandra Denti
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Flavia Ravelli
- Laboratory of Biophysics and Biosignals, University of Trento, Trento, Italy
| |
Collapse
|
|
38
|
McRae C, Kapoor A, Kanda P, Hibbert B, Davis DR. Systematic review of biological therapies for atrial fibrillation. Heart Rhythm 2019; 16:1399-1407. [DOI: 10.1016/j.hrthm.2019.03.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Indexed: 12/09/2022]
|
|
39
|
MicroRNAs: Emerging biomarkers for atrial fibrillation. J Cardiol 2019; 74:475-482. [PMID: 31324570 DOI: 10.1016/j.jjcc.2019.05.018] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/20/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022]
Abstract
Atrial fibrillation (AF) causes severe cardiac dysrhythmia among patients with cardiovascular diseases. AF increases the risk of stroke and heart failure and is a growing public health concern. AF is also associated with various disease conditions such as hypertension, coronary artery disease, aging, and diabetes mellitus. The mechanism underlying AF is not completely understood due to its complexity. However, experimental and clinical data have revealed that the prevalence of this disease is associated with atrial arrhythmogenic remodeling. Currently, there are no biomarkers that are available for the early diagnosis of AF. Several studies have proposed microRNAs (miRNAs) as useful biomarkers for the diagnosis of AF due to their stability and easy availability both in atrial tissue and circulating blood. miRNAs play an important role in the development of the heart. The dysregulation of miRNA expression is associated with cardiac remodeling. Genetic factors strongly contribute to the pathogenesis of AF. Recently, single nucleotide polymorphisms (SNPs) in various genes and miRNAs have been reported to be associated with AF. The aim of this review was to discuss the correlation between SNPs in miRNAs and AF, including those miRNAs that are commonly reported as potential biomarkers for AF.
Collapse
|
|
40
|
Should we abandon the term 〝lone atrial fibrillation〞? Hellenic J Cardiol 2019; 60:216-223. [DOI: 10.1016/j.hjc.2019.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/30/2019] [Accepted: 04/11/2019] [Indexed: 02/01/2023] Open
|
|
41
|
Briasoulis A, Sharma S, Telila T, Mallikethi-Reddy S, Papageorgiou N, Oikonomou E, Tousoulis D. MicroRNAs in Atrial Fibrillation. Curr Med Chem 2019; 26:855-863. [PMID: 28933293 DOI: 10.2174/0929867324666170920151024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/20/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs, involved in regulation of post-transcriptional gene expression. They exert key role not only in physiology and normal development of the cardiovascular system but also in cardiovascular disease development and progression. Recent animal and human studies of tissue specific miRNAs have suggested a role in structural and electrical remodeling in atrial fibrillation (AF). Their emerging role as biomarkers and potential therapeutic targets in patients with AF is discussed in this review.
Collapse
Affiliation(s)
- Alexandros Briasoulis
- Wayne State University, Division of Cardiology, Detroit, Michigan, MI, United States
| | - Shikha Sharma
- University of Michigan, Division of Cardiology, Arrhythmia services, Ann Arbor, Michigan, MI, United States
| | - Tesfaye Telila
- Wayne State University, Division of Cardiology, Detroit, Michigan, MI, United States
| | | | | | - Evangelos Oikonomou
- 1st Department of Cardiology, University of Athens Medical School, Athens, Greece
| | - Dimitris Tousoulis
- 1st Department of Cardiology, University of Athens Medical School, Athens, Greece
| |
Collapse
|
|
42
|
Samal E, Evangelista M, Galang G, Srivastava D, Zhao Y, Vedantham V. Premature MicroRNA-1 Expression Causes Hypoplasia of the Cardiac Ventricular Conduction System. Front Physiol 2019; 10:235. [PMID: 30936836 PMCID: PMC6431665 DOI: 10.3389/fphys.2019.00235] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 02/22/2019] [Indexed: 12/27/2022] Open
Abstract
Mammalian cardiac Purkinje fibers (PFs) are specified from ventricular trabecular myocardium during mid-gestation and undergo limited proliferation before assuming their final form. MicroRNA-1 (miR-1), a negative regulator of proliferation, is normally expressed in the heart at low levels during the period of PF specification and outgrowth, but expression rises steeply after birth, when myocardial proliferation slows and postnatal cardiac maturation and growth commence. Here, we test whether premature up-regulation and overexpression of miR-1 during the period of PF morphogenesis influences PF development and function. Using a mouse model in which miR-1 is expressed under the control of the Myh6 promoter, we demonstrate that premature miR-1 expression leads to PF hypoplasia that persists into adulthood, and miR-1 TG mice exhibit delayed conduction through the ventricular myocardium beginning at neonatal stages. In addition, miR-1 transgenic embryos showed reduced proliferation within the trabecular myocardium and embryonic ventricular conduction system (VCS), a source of progenitor cells for the PF. This repression of proliferation may be mediated by direct translational inhibition by miR-1 of the cyclin dependent kinase Cdk6, a key regulator of embryonic myocardial proliferation. Our results suggest that altering the timing of miR-1 expression can regulate PF development, findings which have implications for our understanding of conduction system development and disease in humans.
Collapse
Affiliation(s)
- Eva Samal
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, United States
| | - Melissa Evangelista
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, United States.,Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Giselle Galang
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, United States.,Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.,Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
| | - Deepak Srivastava
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, United States.,Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States.,Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, United States.,Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
| | - Yong Zhao
- Department of Genetics and Genomic Sciences, Mount Sinai Hospital, New York, NY, United States
| | - Vasanth Vedantham
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, United States.,Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.,Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
| |
Collapse
|
|
43
|
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with pronounced morbidity and mortality. Its prevalence, expected to further increase for the forthcoming years, and associated frequent hospitalizations turn AF into a major health problem. Structural and electrical atrial remodelling underlie the substrate for AF, but the exact mechanisms driving this remodelling remain incompletely understood. Recent studies have shown that microRNAs (miRNA), short non-coding RNAs that regulate gene expression, may be involved in the pathophysiology of AF. MiRNAs have been implicated in AF-induced ion channel remodelling and fibrosis. MiRNAs could therefore provide insight into AF pathophysiology or become novel targets for therapy with miRNA mimics or anti-miRNAs. Moreover, circulating miRNAs have been suggested as a new class of diagnostic and prognostic biomarkers of AF. However, the origin and function of miRNAs in tissue and plasma frequently remain unknown and studies investigating the role of miRNAs in AF vary in design and focus and even present contradicting results. Here, we provide a systematic review of the available clinical and functional studies investigating the tissue and plasma miRNAs in AF and will thereafter discuss the potential of miRNAs as biomarkers or novel therapeutic targets in AF.
Collapse
|
|
44
|
The Clinical Significance of Changes in the Expression Levels of MicroRNA-1 and Inflammatory Factors in the Peripheral Blood of Children with Acute-Stage Asthma. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7632487. [PMID: 30046607 PMCID: PMC6038680 DOI: 10.1155/2018/7632487] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 04/18/2018] [Accepted: 05/07/2018] [Indexed: 12/21/2022]
Abstract
This study assessed the changes and clinical significance of microRNA-1 (miR-1) and inflammatory factors in the peripheral blood of children with acute-stage asthma. 100 children with acute-stage asthma (study group) and 100 healthy children (control group) were enrolled. For all enrolled children, the peripheral blood levels of miR-1, interleukin-4 (IL-4), IL-5, IL-8, tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) were measured. The relative expression levels of miR-1 and IFN-γ in the peripheral blood of children in the study group were significantly lower than those in the control group, whereas expression levels of IL-4, IL-5, IL-8, and TNF-α were significantly higher. Moreover, these levels changed to a greater extent in patients with severe disease (P < 0.05). Further analyses showed that the miR-1 expression level positively correlated with IFN-γ and negatively correlated with IL-4, IL-5, IL-8, and TNF-α expression levels (P < 0.05). ROC curve analysis to identify diagnostic specificity and sensitivity showed that, for diagnosing exacerbation in asthma, the area under the curve (AUC) for miR-1 was the highest (AUC = 0.900, P < 0.05) of all tested markers; this held true for diagnosing severe asthma as well (AUC = 0.977, P < 0.05). Compared to healthy children, children with acute-stage asthma had a low miR-1 expression level and a Th1/Th2 imbalance in their peripheral blood. The changes were closely related, became more exaggerated with an increase in disease severity, and could be used as auxiliary variables for diagnosing asthma exacerbation and evaluating disease severity.
Collapse
|
|
45
|
Tsoporis JN, Fazio A, Rizos IK, Izhar S, Proteau G, Salpeas V, Rigopoulos A, Sakadakis E, Toumpoulis IK, Parker TG. Increased right atrial appendage apoptosis is associated with differential regulation of candidate MicroRNAs 1 and 133A in patients who developed atrial fibrillation after cardiac surgery. J Mol Cell Cardiol 2018; 121:25-32. [PMID: 29885959 DOI: 10.1016/j.yjmcc.2018.06.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 06/01/2018] [Accepted: 06/06/2018] [Indexed: 02/08/2023]
Abstract
Atrial fibrillation (AF) following on-pump coronary artery bypass grafting (CABG) is a common condition associated with increased morbidity and mortality. We investigated the possibility that miRs may play a contributory role in postoperative AF and associated apoptosis. A total of 42 patients (31 males and 11 females, mean age 65.0 ± 1.3 years) with sinus rhythm and without a history of AF were prospectively enrolled. We examined the levels of the muscle-specific miRs 1 and 133A and markers of apoptosis including TUNEL staining, caspase-3 activation, Bcl2 and Bax mRNAs in right atrial appendage (RAA) biopsies and blood plasma taken before aortic cross-clamping and after reperfusion. After reperfusion, indices of apoptosis increased the RAA. There was no change in tissue or plasma miR -1 and -133A levels compared to pre CABG. However, in patients who postoperatively developed AF (n = 14, 7 males and 7 females), compared to patients that remained in SR (n = 28, 24 males and 4 females) post CABG, tissue miR-1 increased whereas miR-133A decreased and negatively correlated with RAA apoptosis. Mechanistically, overexpression of miR-133A inhibited hypoxia-induced rat neonatal cardiomyocyte apoptosis and phosphorylated pro-survival Akt, responses abolished by a miR-133A antisense inhibitor oligonucleotide or by pre-treatment with an Akt inhibitor. In postoperative AF, differential regulation of pro- and anti-apoptotic miRs-1 and -133A respectively in the RAA, may contribute to postoperative apoptosis. These results provide new insights into molecular mechanisms of postoperative AF with potential therapeutic implications.
Collapse
Affiliation(s)
- James N Tsoporis
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Canada.
| | - Anastasia Fazio
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Ioannis K Rizos
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Shehla Izhar
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Canada
| | - Gerald Proteau
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Canada
| | - Vasileos Salpeas
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Angelos Rigopoulos
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Eleftherios Sakadakis
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Ioannis K Toumpoulis
- 2nd Academic Department of Cardiology, Attikon University Hospital, University of Athens Medical School, National and Kapodistrian University of Athens, Greece
| | - Thomas G Parker
- Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Canada
| |
Collapse
|
|
46
|
Wei J, Zhang Y, Li Z, Wang X, Chen L, Du J, Liu J, Liu J, Hou Y. GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial-tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. Pacing Clin Electrophysiol 2018; 41:459-471. [PMID: 29436714 DOI: 10.1111/pace.13289] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/04/2018] [Accepted: 01/15/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS Cardiac autonomic nerve remodeling (ANR) is an important mechanism of atrial fibrillation (AF). GTP cyclohydrolase I, encoded by GCH1, is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthesis. Previous studies reported that increased BH4 and NO content negatively regulated nerve regeneration. This study investigated the effects of GCH1 on ANR via BH4 pathway, regulated by microRNA-206 (miR-206). METHODS AND RESULTS In canines, atrial tachypacing (A-TP), together with miR-206 overexpression, increased PGP9.5 level and inhibited GCH1 expression by quantitative real-time polymerase chain reaction and western blot analysis. GCH1 was validated to be a direct target of miR-206 by luciferase assays. Meanwhile, miR-206 overexpression by lentiviruses infection into right superior pulmonary vein fat pad decreased GCH1 expression to ∼40% and further reduced BH4 and NO content compared with the control canines. After infection of GCH1 overexpression lentiviruses for two weeks, atrial effective refractory period was increased compared with the control group (105.8 ± 1.537 ms vs 99.17 ± 2.007 ms, P < 0.05). Moreover, GCH1 overexpression attenuated canines' atrial PGP9.5 level to ∼56% of the controls. In myocardial cells, transfection of GCH1 overexpression lentiviruses also decreased PGP9.5 expression to 26% of the control group. In patients, plasma was collected and miR-206 expression was upregulated in AF patients (n = 18) than the controls (n = 12). CONCLUSIONS Our findings suggested that GCH1 downregulation exacerbated ANR by decreasing atrial BH4 and NO content modulated by miR-206 in A-TP canines. This indicates that GCH1 may prevent the initiation of AF through inhibiting ANR.
Collapse
Affiliation(s)
- Jinqiu Wei
- Department of Examination Center, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yujiao Zhang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Zhan Li
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ximin Wang
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Linlin Chen
- Department of Special Examination, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Juanjuan Du
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jing Liu
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ju Liu
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yinglong Hou
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, China
| |
Collapse
|
|
47
|
Miguel V, Cui JY, Daimiel L, Espinosa-Díez C, Fernández-Hernando C, Kavanagh TJ, Lamas S. The Role of MicroRNAs in Environmental Risk Factors, Noise-Induced Hearing Loss, and Mental Stress. Antioxid Redox Signal 2018; 28:773-796. [PMID: 28562070 PMCID: PMC5911706 DOI: 10.1089/ars.2017.7175] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on every realm of biomedicine is established and progressively increasing. The impact of environment on human health is enormous. Among environmental risk factors impinging on quality of life are those of chemical nature (toxic chemicals, heavy metals, pollutants, and pesticides) as well as those related to everyday life such as exposure to noise or mental and psychosocial stress. Recent Advances: This review elaborates on the relationship between miRNAs and these environmental risk factors. CRITICAL ISSUES The most relevant facts underlying the role of miRNAs in the response to these environmental stressors, including redox regulatory changes and oxidative stress, are highlighted and discussed. In the cases wherein miRNA mutations are relevant for this response, the pertinent literature is also reviewed. FUTURE DIRECTIONS We conclude that, even though in some cases important advances have been made regarding close correlations between specific miRNAs and biological responses to environmental risk factors, a need for prospective large-cohort studies is likely necessary to establish causative roles. Antioxid. Redox Signal. 28, 773-796.
Collapse
Affiliation(s)
- Verónica Miguel
- 1 Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) , Madrid, Spain
| | - Julia Yue Cui
- 2 Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington
| | - Lidia Daimiel
- 3 Instituto Madrileño de Estudios Avanzados-Alimentación (IMDEA-Food) , Madrid, Spain
| | - Cristina Espinosa-Díez
- 4 Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University , Portland, Oregon
| | | | - Terrance J Kavanagh
- 2 Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington
| | - Santiago Lamas
- 1 Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) , Madrid, Spain
| |
Collapse
|
|
48
|
Lozano-Velasco E, Wangensteen R, Quesada A, Garcia-Padilla C, Osorio JA, Ruiz-Torres MD, Aranega A, Franco D. Hyperthyroidism, but not hypertension, impairs PITX2 expression leading to Wnt-microRNA-ion channel remodeling. PLoS One 2017; 12:e0188473. [PMID: 29194452 PMCID: PMC5711019 DOI: 10.1371/journal.pone.0188473] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 11/07/2017] [Indexed: 01/06/2023] Open
Abstract
PITX2 is a homeobox transcription factor involved in embryonic left/right signaling and more recently has been associated to cardiac arrhythmias. Genome wide association studies have pinpointed PITX2 as a major player underlying atrial fibrillation (AF). We have previously described that PITX2 expression is impaired in AF patients. Furthermore, distinct studies demonstrate that Pitx2 insufficiency leads to complex gene regulatory network remodeling, i.e. Wnt>microRNAs, leading to ion channel impairment and thus to arrhythmogenic events in mice. Whereas large body of evidences has been provided in recent years on PITX2 downstream signaling pathways, scarce information is available on upstream pathways influencing PITX2 in the context of AF. Multiple risk factors are associated to the onset of AF, such as e.g. hypertension (HTN), hyperthyroidism (HTD) and redox homeostasis impairment. In this study we have analyzed whether HTN, HTD and/or redox homeostasis impact on PITX2 and its downstream signaling pathways. Using rat models for spontaneous HTN (SHR) and experimentally-induced HTD we have observed that both cardiovascular risk factors lead to severe Pitx2 downregulation. Interesting HTD, but not SHR, leads to up-regulation of Wnt signaling as well as deregulation of multiple microRNAs and ion channels as previously described in Pitx2 insufficiency models. In addition, redox signaling is impaired in HTD but not SHR, in line with similar findings in atrial-specific Pitx2 deficient mice. In vitro cell culture analyses using gain- and loss-of-function strategies demonstrate that Pitx2, Zfhx3 and Wnt signaling influence redox homeostasis in cardiomyocytes. Thus, redox homeostasis seems to play a pivotal role in this setting, providing a regulatory feedback loop. Overall these data demonstrate that HTD, but not HTN, can impair Pitx2>>Wnt pathway providing thus a molecular link to AF.
Collapse
Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | | | - Andrés Quesada
- Department of Health Sciences, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Julia A. Osorio
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - María Dolores Ruiz-Torres
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia Aranega
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| |
Collapse
|
|
49
|
Wang F, Zhang SJ, Yao X, Tian DM, Zhang KQ, She DM, Guo FF, Zhai QW, Ying H, Xue Y. Circulating microRNA-1a is a biomarker of Graves' disease patients with atrial fibrillation. Endocrine 2017; 57:125-137. [PMID: 28547036 DOI: 10.1007/s12020-017-1331-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 05/15/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE It has been increasingly suggested that specific microRNAs expression profiles in the circulation and atrial tissue are associated with the susceptibility to atrial fibrillation. Nonetheless, the role of circulating microRNAs in Graves' disease patients with atrial fibrillation has not yet been well described. The objective of the study was to identify the role of circulating microRNAs as specific biomarkers for the diagnosis of Graves' disease with atrial fibrillation. METHODS The expression profiles of eight serum microRNAs, which are found to be critical in the pathogenesis of atrial fibrillation, were determined in patients with Graves' disease with or without atrial fibrillation. MicroRNA expression analysis was performed by real-time PCR in normal control subjects (NC; n = 17), patients with Graves' disease without atrial fibrillation (GD; n = 29), patients with Graves' disease with atrial fibrillation (GD + AF; n = 14), and euthyroid patients with atrial fibrillation (AF; n = 22). RESULTS Three of the eight serum microRNAs,i.e., miR-1a, miR-26a, and miR-133, had significantly different expression profiles among the four groups. Spearman's correlation analysis showed that the relative expression level of miR-1a was positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), and negatively related to thyroid stimulating hormone. Spearman's correlations analysis also revealed that the level of miR-1a was negatively correlated with a critical echocardiographic parameter (left atrial diameter), which was dramatically increased in GD + AF group compared to GD group. Furthermore, the receiver-operating characteristic curve analysis indicated that, among the eight microRNAs, miR-1a had the largest area under the receiver-operating characteristic curves not only for discriminating between individuals with and without Graves' disease, but also for predicting the presence of atrial fibrillation in patients with Graves' disease. CONCLUSIONS Our findings showed that the levels of serum miR-1a were significantly decreased in GD + AF group compared with GD group, suggesting that serum miR-1a might serve as a novel biomarker for diagnosis of atrial fibrillation in patients with Graves' disease.
Collapse
Affiliation(s)
- Fang Wang
- Department of Endocrinology, People's Hospital of Shanghai Putuo District, Shanghai, 200060, China
| | - Sheng-Jie Zhang
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xuan Yao
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Dong-Mei Tian
- Department of Endocrinology, People's Hospital of Shanghai Putuo District, Shanghai, 200060, China
| | - Ke-Qin Zhang
- Department of Endocrinology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, 200065, China
| | - Dun-Min She
- Department of Endocrinology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, 200065, China
| | - Fei-Fan Guo
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qi-Wei Zhai
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Hao Ying
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ying Xue
- Department of Endocrinology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, 200065, China.
| |
Collapse
|
|
50
|
de Lucia C, Komici K, Borghetti G, Femminella GD, Bencivenga L, Cannavo A, Corbi G, Ferrara N, Houser SR, Koch WJ, Rengo G. microRNA in Cardiovascular Aging and Age-Related Cardiovascular Diseases. Front Med (Lausanne) 2017; 4:74. [PMID: 28660188 PMCID: PMC5466994 DOI: 10.3389/fmed.2017.00074] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 05/26/2017] [Indexed: 12/17/2022] Open
Abstract
Over the last decades, life expectancy has significantly increased although several chronic diseases persist in the population, with aging as the leading risk factor. Despite improvements in diagnosis and treatment, many elderlies suffer from cardiovascular problems that are much more frequent in an older, more fragile organism. In the long term, age-related cardiovascular diseases (CVDs) contribute to the decline of quality of life and ability to perform normal activities of daily living. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level in both physiological and pathological conditions. In this review, we will focus on the role of miRNAs in aging and age-related CVDs as heart failure, hypertension, atherosclerosis, atrial fibrillation, and diabetes mellitus. miRNAs are key regulators of complex biological mechanisms, representing an exciting potential therapeutic target in CVDs. Moreover, one major challenge in geriatric medicine is to find reliable biomarkers for diagnosis, prognosis, and prediction of the response to specific drugs. miRNAs represent a very promising tool due to their stability in the circulation and unique signature in CVDs. However, further studies are needed to investigate their translational potential in the real clinical practice.
Collapse
Affiliation(s)
- Claudio de Lucia
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.,Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Klara Komici
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Giulia Borghetti
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Grazia Daniela Femminella
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Leonardo Bencivenga
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Alessandro Cannavo
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.,Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Graziamaria Corbi
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | - Nicola Ferrara
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.,Scientific Institute of Telese Terme, Salvatore Maugeri Foundation, IRCCS, Benevento, Italy
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Walter J Koch
- Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Giuseppe Rengo
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.,Scientific Institute of Telese Terme, Salvatore Maugeri Foundation, IRCCS, Benevento, Italy
| |
Collapse
|