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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.
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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
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Jiang Y, Luo B, Chen Y, Lu W, Peng Y, Chen L, Lin Y. Serum calcium-magnesium ratio at admission predicts adverse outcomes in patients with acute coronary syndrome. PLoS One 2024; 19:e0313352. [PMID: 39514617 PMCID: PMC11548839 DOI: 10.1371/journal.pone.0313352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Evidence from observational studies suggests that increased calcium exposure may elevate the risk of adverse events in patients with coronary artery disease, while magnesium may exert a protective effect on disease risk. However, there have been limited investigations into the relationship between these minerals and acute coronary syndrome (ACS). Therefore, this study aimed to explore the association between the Serum calcium-magnesium ratio (Ca/Mg ratio) in patients with acute coronary syndrome and their clinical outcomes. METHODS This retrospective analysis reviewed the clinical data of 1,775 patients with ACS who underwent coronary angiography and/or percutaneous coronary intervention (PCI) at the Fujian Heart Center between May 2017 and December 2022. The patients were categorized into four groups based on their Ca/Mg ratio at admission (Group 1, ≤2.373, n = 443; Group 2, 2.374-2.517, n = 442; Group 3, 2.518-2.675, n = 446; Group 4, ≥2.676, n = 444). Single-factor analysis and multivariate logistic regression were employed to analyze the clinical characteristics and postoperative clinical outcomes of patients in different groups. The primary outcome included major adverse cardiovascular and cerebrovascular events (MACCEs), while the secondary outcomes included contrast-induced nephropathy (CIN)、all-cause rehospitalization raten and hematorrhea. RESULTS Univariate analysis showed that the patients had a mean age of 64.50±10.79 years, with 370 female patients (20.8%). Additionally, 1,158 patients had hypertension (65.2%), and 710 patients had diabetes (40.5%). Univariate analysis showed an inverse relationship between the serum calcium-to-magnesium ratio and all-cause in-hospital mortality, with patients in the lowest quartile having the highest mortality rate. Multivariate analysis showed that the Ca/Mg ratio at admission was independently associated with MACCEs. Among them, this ratio was inversely associated with all-cause mortality [adjusted odds ratio (aOR) 0.07; 95% CI 0.01-0.63; P<0.05] and positively associated with new-onset atrial fibrillation (aOR 1.86; 95% CI 1.08-3.21; P<0.05). Additionally, the Ca/Mg ratio was positively correlated with an increased risk of postoperative major bleeding (aOR 6.58; 95% CI 1.43-30.29; P<0.05). CONCLUSION In this large retrospective study, serum calcium and magnesium levels at admission were significantly associated with adverse outcomes in patients with ACS. The Ca/Mg ratio was identified as a reliable predictor of poor prognosis in ACS patients.
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Affiliation(s)
- Yan Jiang
- School of Nursing, Fujian Medical University, Fuzhou, Fujian, China
| | - Baolin Luo
- Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yaqin Chen
- School of Nursing, Fujian Medical University, Fuzhou, Fujian, China
| | - Wen Lu
- School of Nursing, Fujian Medical University, Fuzhou, Fujian, China
| | - Yanchun Peng
- Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Liangwan Chen
- Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, Fujian, China
| | - Yanjuan Lin
- Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
- Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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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.
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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
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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.
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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;
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Asjad E, Dobrzynski H. MicroRNAs: Midfielders of Cardiac Health, Disease and Treatment. Int J Mol Sci 2023; 24:16207. [PMID: 38003397 PMCID: PMC10671258 DOI: 10.3390/ijms242216207] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/05/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a role in post-transcriptional gene regulation. It is generally accepted that their main mechanism of action is the negative regulation of gene expression, through binding to specific regions in messenger RNA (mRNA) and repressing protein translation. By interrupting protein synthesis, miRNAs can effectively turn genes off and influence many basic processes in the body, such as developmental and apoptotic behaviours of cells and cardiac organogenesis. Their importance is highlighted by inhibiting or overexpressing certain miRNAs, which will be discussed in the context of coronary artery disease, atrial fibrillation, bradycardia, and heart failure. Dysregulated levels of miRNAs in the body can exacerbate or alleviate existing disease, and their omnipresence in the body makes them reliable as quantifiable markers of disease. This review aims to provide a summary of miRNAs as biomarkers and their interactions with targets that affect cardiac health, and intersperse it with current therapeutic knowledge. It intends to succinctly inform on these topics and guide readers toward more comprehensive works if they wish to explore further through a wide-ranging citation list.
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Affiliation(s)
- Emman Asjad
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK;
| | - Halina Dobrzynski
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK;
- Department of Anatomy, Jagiellonian University Medical College, 31-034 Krakow, Poland
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Li N, Wang L, Li L, Yang MZ, Wang QX, Bai XW, Gao F, Yuan YQ, Yu ZJ, Ren ZG. The correlation between gut microbiome and atrial fibrillation: pathophysiology and therapeutic perspectives. Mil Med Res 2023; 10:51. [PMID: 37936201 PMCID: PMC10629124 DOI: 10.1186/s40779-023-00489-1] [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: 05/23/2023] [Accepted: 10/26/2023] [Indexed: 11/09/2023] Open
Abstract
Regulation of gut microbiota and its impact on human health is the theme of intensive research. The incidence and prevalence of atrial fibrillation (AF) are continuously escalating as the global population ages and chronic disease survival rates increase; however, the mechanisms are not entirely clarified. It is gaining awareness that alterations in the assembly, structure, and dynamics of gut microbiota are intimately engaged in the AF progression. Owing to advancements in next-generation sequencing technologies and computational strategies, researchers can explore novel linkages with the genomes, transcriptomes, proteomes, and metabolomes through parallel meta-omics approaches, rendering a panoramic view of the culture-independent microbial investigation. In this review, we summarized the evidence for a bidirectional correlation between AF and the gut microbiome. Furthermore, we proposed the concept of "gut-immune-heart" axis and addressed the direct and indirect causal roots between the gut microbiome and AF. The intricate relationship was unveiled to generate innovative microbiota-based preventive and therapeutic interventions, which shed light on a definite direction for future experiments.
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Affiliation(s)
- Na Li
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China
| | - Ling Wang
- Department of Cardiovascular Medicine, Henan Provincial Chest Hospital, Zhengzhou, 450008, China
| | - Lei Li
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China
| | - Meng-Zhao Yang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China
| | - Qing-Xiang Wang
- Department of Blood Collection, Xuchang Blood Center, Xuchang, 461000, Henan, China
| | - Xi-Wen Bai
- Nanchang University Queen Marry School, Nanchang, 330036, China
| | - Feng Gao
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China
| | - Yi-Qiang Yuan
- Department of Cardiovascular Medicine, Henan Provincial Chest Hospital, Zhengzhou, 450008, China.
| | - Zu-Jiang Yu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Zhi-Gang Ren
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China.
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7
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Kuang Z, Wu J, Tan Y, Zhu G, Li J, Wu M. MicroRNA in the Diagnosis and Treatment of Doxorubicin-Induced Cardiotoxicity. Biomolecules 2023; 13:biom13030568. [PMID: 36979503 PMCID: PMC10046787 DOI: 10.3390/biom13030568] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/12/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is widely applied to the treatment of cancer; however, DOX-induced cardiotoxicity (DIC) limits its clinical therapeutic utility. However, it is difficult to monitor and detect DIC at an early stage using conventional detection methods. Thus, sensitive, accurate, and specific methods of diagnosis and treatment are important in clinical practice. MicroRNAs (miRNAs) belong to non-coding RNAs (ncRNAs) and are stable and easy to detect. Moreover, miRNAs are expected to become biomarkers and therapeutic targets for DIC; thus, there are currently many studies focusing on the role of miRNAs in DIC. In this review, we list the prominent studies on the diagnosis and treatment of miRNAs in DIC, explore the feasibility and difficulties of using miRNAs as diagnostic biomarkers and therapeutic targets, and provide recommendations for future research.
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Affiliation(s)
- Ziyu Kuang
- Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jingyuan Wu
- Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ying Tan
- Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Guanghui Zhu
- Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jie Li
- Oncology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Min Wu
- Cardiovascular Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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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.
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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
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9
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Shintani-Ishida K, Tsurumi R, Ikegaya H. Decrease in the expression of muscle-specific miRNAs, miR-133a and miR-1, in myoblasts with replicative senescence. PLoS One 2023; 18:e0280527. [PMID: 36649291 PMCID: PMC9844915 DOI: 10.1371/journal.pone.0280527] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 12/29/2022] [Indexed: 01/18/2023] Open
Abstract
Muscles that are injured or atrophied by aging undergo myogenic regeneration. Although myoblasts play a pivotal role in myogenic regeneration, their function is impaired with aging. MicroRNAs (miRNAs) are also involved in myogenic regeneration. MiRNA (miR)-1 and miR-133a are muscle-specific miRNAs that control the proliferation and differentiation of myoblasts. In this study, we determined whether miR-1 and miR-133a expression in myoblasts is altered with cellular senescence and involved in senescence-impaired myogenic differentiation. C2C12 murine skeletal myoblasts were converted to a replicative senescent state by culturing to a high passage number. Although miR-1 and miR-133a expression was largely induced during myogenic differentiation, expression was suppressed in cells at high passage numbers (passage 10 and/or passage 20). Although the senescent myoblasts exhibited a deterioration of myogenic differentiation, transfection of miR-1 or miR-133a into myoblasts ameliorated cell fusion. Treatment with the glutaminase 1 inhibitor, BPTES, removed senescent cells from C2C12 myoblasts with a high passage number, whereas myotube formation and miR-133a expression was increased. In addition, primary cultured myoblasts prepared from aged C57BL/6J male mice (20 months old) exhibited a decrease in miR-1 and miR-133a levels compared with younger mice (3 months old). The results suggest that replicative senescence suppresses muscle-specific miRNA expression in myoblasts, which contributes to the senescence-related dysfunction of myogenic regeneration.
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Affiliation(s)
- Kaori Shintani-Ishida
- Department of Forensic Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Riko Tsurumi
- Department of Forensic Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Ikegaya
- Department of Forensic Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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10
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Barbuti A, Baruscotti M, Bucchi A. The “Funny” Pacemaker Current. HEART RATE AND RHYTHM 2023:63-87. [DOI: 10.1007/978-3-031-33588-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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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.
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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.
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12
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Li C, Wang H, Li M, Qiu X, Wang Q, Sun J, Yang M, Feng X, Meng S, Zhang P, Liu B, Li W, Chen M, Zhao Y, Zhang R, Mo B, Zhu Y, Zhou B, Chen M, Liu X, Zhao Y, Shen M, Huang J, Luo L, Wu H, Li YG. Epidemiology of Atrial Fibrillation and Related Myocardial Ischemia or Arrhythmia Events in Chinese Community Population in 2019. Front Cardiovasc Med 2022; 9:821960. [PMID: 35445083 PMCID: PMC9013769 DOI: 10.3389/fcvm.2022.821960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/15/2022] [Indexed: 11/24/2022] Open
Abstract
Background Atrial fibrillation (AF) is the most common arrhythmia, and the incidence increases rapidly all over the world. The global prevalence of AF (age-adjusted) is 0.60% for men and 0.37% for women and the prevalence of AF in China is 0.65%. It is expected that the number of patients with AF will continue to rise in the future worldwide due to population aging. Objective To explore the prevalence of AF in Chinese community population in 2019 and clarify the prevalence of AF complicated with other arrhythmias and myocardial ischemia (MI) events. Methods The remote electrocardiogram (ECG) diagnosis system of Xinhua Hospital was assessed to the screen participants with ECG evidence of AF between January 1 and December 31, 2019. The prevalence rates of AF and its association with other arrhythmias and MI events were analyzed and subgroup analysis was performed between different sexes and age groups. Results A total of 22,016 AF cases were identified out of all ECGs derived from the remote ECG diagnosis system in 2019. It is estimated that AF was presented in nearly 10.15 million people in China (age-adjusted standardized rate 0.72%, 95% CI 0.20–1.25%) in 2019 and 62% of the AF cases (6.27 million) affected people aged 65 years and above (age-adjusted standardized rate 3.56%, 95% CI 3.28–3.85%). The prevalence rate of AF in males was higher than that in females (p < 0.001), and the ventricular rate of AF patients was faster in females (p < 0.001) and younger patients (p < 0.001). AF patients with lower ventricular rate (under 60 beats per min) were associated with increased prevalence of ventricular escape/escape rhythm [p < 0.001, odds ratio (OR) 5.14] and third-degree atrioventricular block (p < 0.001, OR 32.05). Conclusion The prevalence of AF is higher in the Chinese community population than that was previously reported. AF patients complicated with ECG patterns suggesting myocardial infarction is common in men, and stricter measures should be taken to control the common risk factors of AF and coronary heart disease. It is also important that more attention should be paid to recognize fatal arrhythmias, especially in elderly male patients with AF.
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Affiliation(s)
- Cheng Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haicheng Wang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mohan Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangjun Qiu
- Shanghai Siwei Medical Co. Ltd., Shanghai, China
| | - Qunshan Wang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Sun
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mei Yang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangfei Feng
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu Meng
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pengpai Zhang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Liu
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mu Chen
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Zhao
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Zhang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Binfeng Mo
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuling Zhu
- Shanghai Siwei Medical Co. Ltd., Shanghai, China
| | - Baohong Zhou
- Shanghai Siwei Medical Co. Ltd., Shanghai, China
| | - Min Chen
- Shanghai Siwei Medical Co. Ltd., Shanghai, China
| | - Xia Liu
- Medical Information Telemonitoring Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuelin Zhao
- Medical Information Telemonitoring Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingzhen Shen
- Medical Information Telemonitoring Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinkang Huang
- Medical Information Telemonitoring Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Luo
- School of Public Health, Fudan University, Shanghai, China
| | - Hong Wu
- Shanghai Municipal Health Commission, Shanghai, China
| | - Yi-Gang Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Medical Information Telemonitoring Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yi-Gang Li,
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Yuan K, Zhao P, Wang L. Molecular mechanism of atrial remodeling in patients with aging atrial fibrillation under the expression of microRNA-1 and microRNA-21. Bioengineered 2021; 12:12905-12916. [PMID: 34957910 PMCID: PMC8810186 DOI: 10.1080/21655979.2021.2008668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We investigated the expression levels of microRNA-1 (miRNA-1) and microRNA-21 (miRNA-21) in the atrial tissues of patients with atrial fibrillation (AF) and the molecular mechanism of action in atrial remodeling. Patients with valvular heart disease were selected as the subjects. The ultrastructure, degree of myocardial fibrosis, apoptosis index (AI), expression of microRNA-1, expression of microRNA-21, and mRNA of TIMP-1, MMP-9, BCL-2, and Bax of patients were compared and analyzed in each group. The results showed that the degree of myocardial fibrosis and AI in patients with AF of the same age were extremely higher than those of patients with sinus rhythm (SR) (P < 0.01). Patients with AF showed much higher messenger RNA (mRNA) levels of mini-mental Parkinson 9 (MMP9) and Bax and obvious lover mRNA levels of tissue inhibitors of metalloproteinase 1 (TIMP-1) and Bcl-2 compared with patients with sinus rhythm (SR) (P < 0.05). It indicated that the expression of miRNA-1 in the AF patients was markedly down-regulated, and that miRNA-21 was up-regulated. This showed that microRNA-1 and microRNA-21 were involved in the molecular remodeling of aging AF through the regulation of primers, which would provide a critical basis for diagnosis and treatment of aging AF.
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Affiliation(s)
- Kexin Yuan
- Department of Cardiovascular, Hebei People's Hospital, Shijiazhuang, China
| | - Pei Zhao
- Department of Laboratory Medicine, Hebei People's Hospital, Shijiazhuang, China
| | - Lili Wang
- Department of Cardiovascular, Hebei People's Hospital, Shijiazhuang, China
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14
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Integrative Bioinformatics Analysis Reveals That Infarct-Mediated Overexpression of Potential miR-662/CREB1 Pathway-Induced Neuropeptide VIP Is Associated with the Risk of Atrial Fibrillation: A Correlation Analysis between Myocardial Electrophysiology and Neuroendocrine. DISEASE MARKERS 2021; 2021:8116633. [PMID: 34853624 PMCID: PMC8629660 DOI: 10.1155/2021/8116633] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 11/17/2022]
Abstract
Background Neuropeptide levels are closely associated with the development and maintenance of atrial fibrillation (AF) after myocardial infarction (MI). This study was aimed at investigating the regulatory network that affects neuropeptide expression through transcription factor modulation. Methods We downloaded three datasets from the GEO database, and after performing differential and crosstabulation analyses, we screened out differentially expressed (DE) miRNAs and DEmRNAs coexpressed in AF and MI and performed DEmiRNA–DEmRNA pairing prediction; from which, we constructed a regulatory network. Subsequently, the hsa-miR-662-CREB1-VIP axis was obtained, and the role of CREB1 and VIP in the development of AF after MI was further revealed by single-cell analysis and prediction model construction. Results In this study, eight DEmRNAs and four miRNAs were screened. hsa-miR-662 was identified by database integration analysis to regulate the transcription factor CREB1, a potential transcriptional regulator in VIP. CREB1 and VIP are mainly enriched in pathways of energy metabolism, ion channels, and myocardial contraction. CREB1 and VIP were identified as biomarkers of the onset and prognosis of MI and AF. Conclusions In this study, the miR-662/CREB1/VIP regulatory pathway was constructed through integrated analysis of datasets, thus providing new ideas to study the mechanisms of AF development.
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15
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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.
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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
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16
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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.
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17
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Kuzmin VS, Ivanova AD, Filatova TS, Pustovit KB, Kobylina AA, Atkinson AJ, Petkova M, Voronkov YI, Abramochkin DV, Dobrzynski H. Micro-RNA 133a-3p induces repolarization abnormalities in atrial myocardium and modulates ventricular electrophysiology affecting I Ca,L and Ito currents. Eur J Pharmacol 2021; 908:174369. [PMID: 34310913 DOI: 10.1016/j.ejphar.2021.174369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 07/16/2021] [Accepted: 07/21/2021] [Indexed: 01/04/2023]
Abstract
Mir-133a-3p is the most abundant myocardial microRNA. The impact of mir-133a-3p on cardiac electrophysiology is poorly explored. In this study, we investigated the effects of mir-133a-3p on the main ionic currents critical for action potential (AP) generation and electrical activity of the heart. We used conventional ECG, sharp microelectrodes and patch-clamp to clarify a role of mir-133a-3p in normal cardiac electrophysiology in rats after in vivo and in vitro transfection. Mir-133a-3p caused no changes to pacemaker APs and automaticity in the sinoatrial node. No significant changes in heart rate (HR) were observed in vivo; however, miR transfection facilitated HR increase in response to β-adrenergic stimulation. Mir-133a-3p induced repolarization abnormalities in the atrial working myocardium and the L-type calcium current (ICa,L) was significantly increased. The main repolarization currents, including the transient outward (Ito), ultra-rapid (IK,ur), and inward rectifier (IK1) remained unaffected in atrial cardiomyocytes. Mir-133a-3p affected both ICa,L and Ito in ventricular cardiomyocytes. Systemic administration of mir-133a-3p induced QT-interval prolongation. Bioinformatic analysis revealed protein phosphatase 2 (PPP2CA/B) and Kcnd3 (encoding Kv4.3 channels generating Ito) as the main miR-133a-3p targets in the heart. No changes in mRNA expression of Cacna1c (encoding Cav1.2 channels generating ICa,L) and Kcnd3 were seen in mir-133a-3p treated rats. However, the expression of Ppp2cA, encoding PPP2CA, and Kcnip2 encoding KChIP2, a Kv4.3 regulatory protein, were significantly decreased. The accumulation of mir-133a-3p in cardiac myocytes causes chamber-specific electrophysiological changes. The suppression of PPP2CA, involved in adrenergic signal transduction, and Kchip2 may indirectly mediate mir-133a-3p-induced augmentation of ICa,L and attenuation of Ito.
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Affiliation(s)
- Vladislav S Kuzmin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia.
| | - Alexandra D Ivanova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Tatiana S Filatova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia
| | - Ksenia B Pustovit
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Anastasia A Kobylina
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia
| | - Andrew J Atkinson
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Maria Petkova
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Yurij I Voronkov
- State Research Center of the Russian Federation, Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia
| | - Denis V Abramochkin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Moscow, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Cardiological Complex (NMRCC), Institute of Experimental Cardiology, Moscow, Russia
| | - Halina Dobrzynski
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Heart Embryology and Anatomy Research Team, Department of Anatomy, Jagiellonian University Medical College, Cracow, Poland
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18
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MicroRNAs and Calcium Signaling in Heart Disease. Int J Mol Sci 2021; 22:ijms221910582. [PMID: 34638924 PMCID: PMC8508866 DOI: 10.3390/ijms221910582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 01/02/2023] Open
Abstract
In hearts, calcium (Ca2+) signaling is a crucial regulatory mechanism of muscle contraction and electrical signals that determine heart rhythm and control cell growth. Ca2+ signals must be tightly controlled for a healthy heart, and the impairment of Ca2+ handling proteins is a key hallmark of heart disease. The discovery of microRNA (miRNAs) as a new class of gene regulators has greatly expanded our understanding of the controlling module of cardiac Ca2+ cycling. Furthermore, many studies have explored the involvement of miRNAs in heart diseases. In this review, we aim to summarize cardiac Ca2+ signaling and Ca2+-related miRNAs in pathological conditions, including cardiac hypertrophy, heart failure, myocardial infarction, and atrial fibrillation. We also discuss the therapeutic potential of Ca2+-related miRNAs as a new target for the treatment of heart diseases.
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19
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Expression levels of serum circulating microRNAs in pediatric patients with ventricular and supraventricular arrhythmias. Adv Med Sci 2021; 66:411-417. [PMID: 34509057 DOI: 10.1016/j.advms.2021.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Aberrant expression of various miRNA species has been implicated in numerous cardiac diseases, e.g., heart failure, hypertrophy, conduction disturbances, and arrhythmogenesis. The aim of this study was to determine whether miR-1, miR-133a, and miR-133b can serve as biomarkers in the diagnosis of ventricular (Va) and supraventricular (SVa) arrhythmias in pediatric patients. MATERIALS AND METHODS Molecular analysis included 30 patients with SVa or Va (13-17.5 years; 14 boys/16 girls) and 20 non-arrhythmic controls. Arrhythmia was confirmed by 24-h Holter ECG recording. miRNA was extracted from serum using the miRNeasyR Serum/Plasma Kit. miScript SYBR Green PCR Kit (Qiagen) was used to quantify miRNA expression. RESULTS The levels of miR-1 and miR-133a expression were significantly higher in the SVa group than in the controls (p = 0.0327 and p<0.0001, respectively). Additionally, both groups of patients with arrhythmia presented significantly lower expression levels of miR-133b than the controls (p<0.01 for both comparisons). The level of miR-133a expression in the SVa group was significantly higher than in the Va group (p = 0.0124). ROC analysis demonstrated that the expressions of miR-1 and miR-133a could differentiate between the SVa patients and arrhythmia-free controls (AUC = 0.7091, p = 0.07 and AUC = 0.8021, p = 0.007, respectively). Furthermore, the expression of miR-133b was shown to distinguish patients with SVa and Va from the arrhythmia-free controls (AUC = 0.7273, p = 0.07 and AUC = 0.8030, p = 0.04, respectively). CONCLUSIONS miR-1, miR-133a, and miR-133b have the potential to become diagnostic biomarkers of arrhythmia in pediatric patients.
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Mohammadi A, Balizadeh Karami AR, Dehghan Mashtani V, Sahraei T, Bandani Tarashoki Z, Khattavian E, Mobarak S, Moradi Kazerouni H, Radmanesh E. Evaluation of Oxidative Stress, Apoptosis, and Expression of MicroRNA-208a and MicroRNA-1 in Cardiovascular Patients. Rep Biochem Mol Biol 2021; 10:183-196. [PMID: 34604408 PMCID: PMC8480300 DOI: 10.52547/rbmb.10.2.183] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 02/15/2021] [Indexed: 04/25/2023]
Abstract
BACKGROUND MicroRNA expression signature and reactive oxygen species (ROS) production have been associated with the development of cardiovascular diseases (CVDs). This study aimed to evaluate oxidative stress, inflammation, apoptosis, and the expression of miRNA-208a and miRNA-1 in cardiovascular patients. METHODS The study population included four types of patients (acute coronary syndromes (ACS), myocardial infarction (MI), arrhythmia, and heart failure (HF)), with 10 people in each group, as well as a control group. Quantitative real-time PCR was performed to measure mir-208 and miR-1 expression, the mRNAs of inflammatory mediators (TNFα, iNOS/eNOS), and apoptotic factors (Bax and Bcl2). XOX, MDA, and antioxidant enzymes (CAT, SOD, and GPx) were measured by ZellBio GmbH kits by an ELISA Reader. RESULTS The results showed significant decreases in the activity of antioxidant enzymes (CAT, SOD, and Gpx) and a significant increase in the activity of the MDA and XOX in cardiovascular patients. Significant increases in IL-10, iNos, iNOS / eNOS, and TNF-α in cardiovascular patients were also observed. Also, a significant increase in the expression of miR-208 (HF> arrhythmia> ACS> MI) and a significant decrease in the expression of miR-1 (ACS> arrhythmia> HF> MI) were found in all four groups in cardiovascular patients. CONCLUSION The results showed increases in oxidative stress, inflammation, apoptotic factors, and in the expression of miR-208a in a variety of cardiovascular patients (ACS, MI, arrhythmia, and HF). It is suggested that future studies determine the relationships that miR-1, miR-208, and oxidative stress indices have with inflammation and apoptosis.
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Affiliation(s)
| | | | | | | | | | - Ehsan Khattavian
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran.
| | - Sara Mobarak
- Abadan Faculty of Medical Sciences, Abadan, Iran.
| | | | - Esmat Radmanesh
- Abadan Faculty of Medical Sciences, Abadan, Iran.
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran.
- Corresponding author: Esmat Radmanesh; Tel: +98 9171438307; E-mail:
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21
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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.
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22
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Hadova K, Kralova E, Doka G, Bies Pivackova L, Kmecova Z, Krenek P, Klimas J. Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy. BMC Cardiovasc Disord 2021; 21:118. [PMID: 33653265 PMCID: PMC7927235 DOI: 10.1186/s12872-021-01929-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/11/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia. METHODS Diabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro. RESULTS Six weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP). CONCLUSIONS This result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.
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Affiliation(s)
- Katarina Hadova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Eva Kralova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Gabriel Doka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Lenka Bies Pivackova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Zuzana Kmecova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Peter Krenek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovakia.
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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]
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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.
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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
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25
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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
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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.
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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
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Nattel S, Heijman J, Zhou L, Dobrev D. Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective. Circ Res 2020; 127:51-72. [PMID: 32717172 PMCID: PMC7398486 DOI: 10.1161/circresaha.120.316363] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options. A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms. This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation. We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF. We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na+-channel dysfunction), electrical refractoriness, and impulse generation. We then consider the molecular drivers of AF progression, including a range of Ca2+-dependent intracellular processes, microRNA changes, and inflammatory signaling. The concept of key interactome-related nodal points is then evaluated, dealing with systems like those associated with CaMKII (Ca2+/calmodulin-dependent protein kinase-II), NLRP3 (NACHT, LRR, and PYD domains-containing protein-3), and transcription-factors like TBX5 and PitX2c. We conclude with a critical discussion of therapeutic implications, knowledge gaps and future directions, dealing with such aspects as drug repurposing, biologicals, multispecific drugs, the targeting of cardiomyocyte inflammatory signaling and potential considerations in intervening at the level of interactomes and gene-regulation. The area of molecular intervention for AF management presents exciting new opportunities, along with substantial challenges.
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Affiliation(s)
- Stanley Nattel
- Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
- IHU Liryc and Fondation Bordeaux Université, Bordeaux, France
| | - Jordi Heijman
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Liping Zhou
- Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada
| | - Dobromir Dobrev
- Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
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28
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Nader J, Metzinger L, Maitrias P, Caus T, Metzinger-Le Meuth V. Aortic valve calcification in the era of non-coding RNAs: The revolution to come in aortic stenosis management? Noncoding RNA Res 2020; 5:41-47. [PMID: 32195449 PMCID: PMC7075756 DOI: 10.1016/j.ncrna.2020.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/04/2020] [Accepted: 02/24/2020] [Indexed: 01/08/2023] Open
Abstract
Aortic valve stenosis remains the most frequent structural heart disease, especially in the elderly. During the last decade, we noticed an important consideration and a huge number of publications related to the medical and surgical treatment of this disease. However, the molecular aspect of this degenerative issue has also been more widely studied recently. As evidenced in oncologic but also cardiac research fields, the emergence of microRNAs in the molecular screening and follow-up makes them potential biomarkers in the future, for the diagnosis, follow-up and treatment of aortic stenosis. Herein, we present a review on the implication of microRNAs in the aortic valve disease management. After listing and describing the main miRNAs of interest in the field, we provide an outline to develop miRNAs as innovative biomarkers and innovative therapeutic strategies, and describe a groundbreaking pre-clinical study using inhibitors of miR-34a in a pre-clinical model of aortic valve stenosis.
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Affiliation(s)
- Joseph Nader
- Department of Cardiac Surgery, Amiens University Hospital, Amiens, France
| | - Laurent Metzinger
- HEMATIM EA4666, C.U.R.S, Université de Picardie Jules Verne, 80025, AMIENS Cedex 1, France
| | - Pierre Maitrias
- Department of Vascular Surgery, Polyclinique Saint Côme, Compiègne, France
| | - Thierry Caus
- Department of Cardiac Surgery, Amiens University Hospital, Amiens, France
| | - Valérie Metzinger-Le Meuth
- HEMATIM EA4666, C.U.R.S, Université de Picardie Jules Verne, 80025, AMIENS Cedex 1, France.,INSERM U1148, Laboratory for Vascular Translational Science (LVTS), UFR SMBH, Université Paris 13-Sorbonne Paris Cité, 93017, BOBIGNY CEDEX, France
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Abstract
A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work.
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Affiliation(s)
- Colin H Peters
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA; , ,
| | - Emily J Sharpe
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA; , ,
| | - Catherine Proenza
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA; , ,
- Department of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
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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.
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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
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31
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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.
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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.
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32
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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.
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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
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Cheng W, Kao Y, Chao T, Lin Y, Chen S, Chen Y. MicroRNA-133 suppresses ZFHX3-dependent atrial remodelling and arrhythmia. Acta Physiol (Oxf) 2019; 227:e13322. [PMID: 31152485 DOI: 10.1111/apha.13322] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 05/16/2019] [Accepted: 05/28/2019] [Indexed: 01/26/2023]
Abstract
AIM Atrial fibrillation (AF) is an important cause of morbidity and mortality in the modern world. Loss-of-function mutation in the zinc finger homeobox 3 gene (ZFHX3) is associated with increased risk of AF. MicroRNAs (miRNAs) participate in arrhythmogenesis, and thus miRNA modulators may be applicable as therapeutic modalities for AF. However, the altered miRNA profiles after ZFHX3 knockdown (KD) remain unclear. This study aimed to analyse the changes of miRNA expression in loss-of-function of ZFHX3 and the effect of miRNA modulation on atrial arrhythmias in this model. METHODS We performed small RNA deep sequencing on ZFHX3-KD and control HL-1 mouse atrial myocytes. The effect of miRNAs on ZFHX3-dependent atrial arrhythmia was evaluated through in vitro and in vivo assays in mice. RESULTS Among the differentially expressed miRNAs, 11 were down-regulated and 6 were up-regulated after ZFHX3 KD. Quantitative real-time PCR analysis confirmed that after ZFHX3 KD, miR-133a and miR-133b were significantly down-regulated, whereas miR-184 was the most significantly up-regulated. DIANA-miRPath analysis suggested that miR-133a/b down-regulation increases the targeted signalling of miR-133 (ie, adrenergic, Wnt/calcium and fibroblast growth factor receptor 1 signalling), which could contribute to pathological remodelling of cardiomyocytes. These results were confirmed through Western blotting. After transfection of miR-133a/b mimics in ZFHX3-KD cells, miR-133a/b levels increased, accompanied by the inhibition of their target signalling. Treatment with miR-133a/b mimics diminished ZFHX3 KD-induced atrial ectopy in mice. CONCLUSION ZFHX3-KD promotes distinct miRNA expressional changes in atrial myocytes. MiR-133a/b mimics may reverse signalling of ZFHX3 KD-mediated cardiac remodelling and atrial arrhythmia.
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Affiliation(s)
- Wan‐Li Cheng
- Graduate Institute of Clinical Medicine, College of Medicine Taipei Medical University Taipei Taiwan
| | - Yu‐Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- Department of Medical Education and Research, Wan Fang Hospital Taipei Medical University Taipei Taiwan
| | - Tze‐Fan Chao
- Division of Cardiology and Cardiovascular Research Center Taipei Veterans General Hospital Taipei Taiwan
| | - Yung‐Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital Taipei Medical University Taipei Taiwan
| | - Shih‐Ann Chen
- Division of Cardiology and Cardiovascular Research Center Taipei Veterans General Hospital Taipei Taiwan
- School of Medicine National Yang‐Ming University Taipei Taiwan
| | - Yi‐Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine Taipei Medical University Taipei Taiwan
- Cardiovascular Research Center, Wan Fang Hospital Taipei Medical University Taipei Taiwan
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Pinchi E, Frati P, Aromatario M, Cipolloni L, Fabbri M, La Russa R, Maiese A, Neri M, Santurro A, Scopetti M, Viola RV, Turillazzi E, Fineschi V. miR-1, miR-499 and miR-208 are sensitive markers to diagnose sudden death due to early acute myocardial infarction. J Cell Mol Med 2019; 23:6005-6016. [PMID: 31240830 PMCID: PMC6714215 DOI: 10.1111/jcmm.14463] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 05/02/2019] [Accepted: 05/15/2019] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are strongly up-regulated under pathological stress and in a wide range of diseases. In recent years, miRNAs are under investigation for their potential use as biomarkers in cardiovascular diseases. We investigate whether specific cardio-miRNAs are overexpressed in heart samples from subjects deceased for acute myocardial infarction (AMI) or sudden cardiac death (SCD), and whether miRNA could help differentiate between them. Forty four cases of death due to cardiovascular disease were selected, respectively, 19 cases categorized as AMI and 25 as SCD. Eighteen cases of traumatic death without pathological cardiac involvement were selected as control. Immunohistochemical investigation was performed for CD15, IL-15, Cx43, MCP-1, tryptase, troponin C and troponin I. Reverse transcription and quantitative real-time PCR were performed for miR-1, miR-133, miR-208 and miR-499. In AMI group, stronger immunoreaction for the CD15, IL-15 and MCP-1 antibodies was detectable compared with SCD and control. Cx43 showed a negative reaction with respect to the other groups. Real-time PCR results showed a down-regulation of all miRNAs in the AMI group compared with SCD and control. The selected miRNAs presented high accuracy in discriminating SCD from AMI (miR-1 and miR-499) and AMI from control (miR-208) representing a potential aid for both clinicians and pathologists for differential diagnosis.
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Affiliation(s)
- Enrica Pinchi
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Paola Frati
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
- IRCSS Neuromed Mediterranean Neurological InstitutePozzilliItaly
| | - Mariarosaria Aromatario
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Luigi Cipolloni
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Matteo Fabbri
- Department of Morphology, Experimental Medicine and SurgeryUniversity of FerraraFerraraItaly
| | - Raffaele La Russa
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
- IRCSS Neuromed Mediterranean Neurological InstitutePozzilliItaly
| | - Aniello Maiese
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Margherita Neri
- Department of Morphology, Experimental Medicine and SurgeryUniversity of FerraraFerraraItaly
| | - Alessandro Santurro
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Matteo Scopetti
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Rocco Valerio Viola
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
| | - Emanuela Turillazzi
- Institute of Legal Medicine, Department of Surgical, Medical and Molecular Pathology and Critical Care MedicineUniversity of PisaPisaItaly
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopaedic SciencesSapienza University of RomeRomeItaly
- IRCSS Neuromed Mediterranean Neurological InstitutePozzilliItaly
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Li MCH, O'Brien TJ, Todaro M, Powell KL. Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance. Epilepsia 2019; 60:1753-1767. [PMID: 31353444 DOI: 10.1111/epi.16301] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 07/07/2019] [Accepted: 07/07/2019] [Indexed: 12/13/2022]
Abstract
There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage-gated sodium channels (Nav 1.1, Nav 1.5), voltage-gated potassium channels (Kv 4.2, Kv 4.3), sodium-calcium exchangers (NCX1), and nonspecific cation-conducting channels (HCN2, HCN4). The pathophysiology may involve autonomic dysfunction and structural cardiac disease, as both are independently associated with epilepsy and ion channel dysregulation. Indeed, in vivo and in vitro studies of cardiac pathology reveal a complex network of signaling pathways and transcription factors regulating ion channel expression in the setting of sympathetic overactivity, cardiac failure, and hypertrophy. Other mechanisms such as circulating inflammatory mediators or exogenous effects of antiepileptic medications lack evidence. Moreover, an acquired cardiac channelopathy may underlie the electrophysiologic cardiac abnormalities seen in chronic epilepsy, potentially contributing to the increased risk of malignant arrhythmias and sudden death. Therefore, further investigation is necessary to establish whether cardiac ion channel dysregulation similarly occurs in patients with epilepsy, and to characterize any pathogenic relationship with SUDEP.
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Affiliation(s)
- Michael C H Li
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Marian Todaro
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.,Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Kim L Powell
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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36
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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.
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37
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Altered biogenesis of microRNA-1 is associated with cardiac dysfunction in aging of spontaneously hypertensive rats. Mol Cell Biochem 2019; 459:73-82. [PMID: 31104265 DOI: 10.1007/s11010-019-03551-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 05/04/2019] [Indexed: 12/19/2022]
Abstract
Currently we face the issues of aging-associated pathologies, particularly those leading to heart failure. With that in mind, in current research we focus on aging and hypertension combination as a widely spread threating problem. In a row with functional and morphological characterization of these aging- and hypertension-associated cardiac changes, we evaluate biogenesis of microRNA-1 being one of major microRNAs in the heart. The aim of this study was to check the hypothesis if dysregulation of microRNA-1 biogenesis is associated with heart failure in aged and especially aged hypertensive rats. The experiments were carried out on male SHR and Wistar rats of age 6 months (young) and 18 months (old). The evaluation of hemodynamic parameters was performed in heart left ventricles of narcotized rats using the ultra-small 2F catheter. The development of fibrosis was determined using light and electron microscopy. Levels of mature and immature forms of microRNA-1 and mRNA encoding the proteins involved in its biogenesis were determined using reverse transcription and quantitative PCR. Aging of both Wistar and SHRs is accompanied with altered hemodynamic parameters compared with correspondent younger mates. SHRs, especially old ones, demonstrated significant heart fibrosis. In aged animals, the level of primary microRNA-1 in Wistar rats were 7 times higher (p < 0.05) and in SHR 17 times higher (p < 0.05) in comparison with young rats of the same strain. We also observed 22 times higher level of immature microRNA-1 in the heart of Wistar and 5.9 times higher level for aged hypertensive rats (p < 0.05) compared to young rats. At the same time, the level of mature microRNA-1 occurred 2.5 and 3.2 times lower in respective groups (p < 0.05). In the current study, we observe the significant dysregulation of microRNA-1 processing in the heart associated with aging and arterial hypertension.
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Li W, Liu M, Zhao C, Chen C, Kong Q, Cai Z, Li D. MiR-1/133 attenuates cardiomyocyte apoptosis and electrical remodeling in mice with viral myocarditis. Cardiol J 2019; 27:285-294. [PMID: 30994182 DOI: 10.5603/cj.a2019.0036] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 09/28/2018] [Accepted: 09/28/2018] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The role of miR-1 and miR-133 in regulating the expression of potassium and calcium ion channels, and mediating cardiomyocyte apoptosis in mice with viral myocarditis (VMC) is investigated herein. METHODS Male Balb/c mice were randomly divided into groups: control group, VMC group, VMC + miR-1/133 mimics group, or VMC + miR-1/133 negative control (NC) group. VMC was induced with coxsackievirus B3 (CVB3). MiR-1/133 mimics ameliorated cardiac dysfunction in VMC mice and was compared to the VMC+NC group. RESULTS Hematoxylin and eosin staining showed a well-arranged myocardium without inflammatory cell infiltration in the myocardial matrix of the control group. However, in the VMC and VMC+NC groups, the myocardium was disorganized and swollen with necrosis, and the myocardial matrix was infiltrated with inflammatory cells. These changes were alleviated by miR-1/133 mimics. TUNEL staining revealed decreased cardiomyocyte apoptosis in the VMC + miR-1/133 mimics group compared with the VMC group. In addition, miR-1/133 mimics up-regulated the expression of miR-1 and miR-133, the potassium channel genes Kcnd2 and Kcnj2, as well as Bcl-2, and down-regulated the expression of the potassium channel suppressor gene Irx5, L-type calcium channel subunit gene a1c (Cacna1c), Bax, and caspase-9 in the myocardium of VMC mice. MiR-1/133 also up-regulated the protein levels of Kv4.2 and Kir2.1, and down-regulated the expression of CaV1.2 in the myocardium of VMC mice. CONCLUSIONS MiR-1 and miR-133 decreased cardiomyocyte apoptosis by mediating the expression of apoptosis-related genes in the hearts of VMC mice.
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Affiliation(s)
- Wei Li
- Biomedical Engineering Institute, School of Control Science and Engineering, Shandong University, Jinan, China
| | - Mengmeng Liu
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Cuifen Zhao
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
| | - Cai Chen
- Biomedical Engineering Institute, School of Control Science and Engineering, Shandong University, Jinan, China
| | - Qingyu Kong
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Zhifeng Cai
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Dong Li
- Research Room of Hypothermia Medicine, Qilu Hospital of Shandong University, Jinan, China
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Moreno EC, Pascual A, Prieto-Cuadra D, Laza VF, Molina-Cerrillo J, Ramos-Muñoz ME, Rodríguez-Serrano EM, Soto JL, Carrato A, García-Bermejo ML, Guillén-Ponce C. Novel Molecular Characterization of Colorectal Primary Tumors Based on miRNAs. Cancers (Basel) 2019; 11:cancers11030346. [PMID: 30862091 PMCID: PMC6468580 DOI: 10.3390/cancers11030346] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/05/2019] [Accepted: 03/06/2019] [Indexed: 12/13/2022] Open
Abstract
microRNAs (miRNA) expression in colorectal (CR) primary tumours can facilitate a more precise molecular characterization. We identified and validated a miRNA profile associated with clinical and histopathological features that might be useful for patient stratification. In situ hybridization array using paraffin-embedded biopsies of CR primary tumours were used to screen 1436 miRNAs. 17 miRNAs were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 192) and were further correlated with clinical and histopathological data. We demonstrated that miRNAs associated to Colorectal Cancer (CRC) diagnosis age (over 50s and 60s) included miR-1-3p, miR-23b-3p, miR-27b-3p, miR-143-3p, miR-145-5p and miR-193b-5p. miR-23b-3p and miR-24-3p discriminated between Lynch Syndrome and sporadic CRC. miR-10a-5p, miR-20a-5p, miR-642b and Let-7a-5p were associated to stroma abundance. miR-642b and Let-7a-5p were associated with to peritumoral inflammation abundance. miR-1-3p, miR-143-3p and miR-145-5p correlated with mucinous component. miR-326 correlated with tumour location (right or left sided). miR-1-3p associated with tumour grade. miR-20a-5p, miR-193b-5p, miR-320a, miR-326 and miR-642b-3p associated to tumour stage and progression. Remarkably, we also demonstrated that miR-1-3p and miR-326 expression significantly associated with patient overall survival (OS). Hierarchical clustering and bioinformatics analysis indicated that selected miRNAs could re-classify the patients and work cooperatively, modulating common target genes involved in colorectal cancer key signalling pathways. In conclusion, molecular characterization of CR primary tumours based on miRNAs could lead to more accurate patient reclassification and may be useful for efficient patient management.
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Affiliation(s)
- Elisa Conde Moreno
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Alejandro Pascual
- Pathology Department, Ramon y Cajal Research Institute, University Hospital, 28034 Madrid, Spain.
| | - Daniel Prieto-Cuadra
- SynlabPathology, Pathology Department, Virgen de la Victoria, University Hospital, 29010 Málaga, Spain.
| | - Val F Laza
- Microbiology Department and Bioinformatics Core Facility, IRYCIS, 28034 Madrid, Spain.
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
| | - Miren Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | | | - José Luis Soto
- Hereditary Cancer Program Valencian Region, Molecular Genetics Laboratory, Elche University Hospital, Elche, 03202 Alicante, Spain.
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, Alcala University, 28034 Ciberonc, Spain.
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Ramon y Cajal Research Institute, (IRYCIS), 28034 Madrid, RedinRen, Spain.
| | - Carmen Guillén-Ponce
- Medical Oncology Department, Ramon y Cajal Research Institute, University Hospital, IRYCIS, 28034 Madrid, Spain.
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Qin R, Murakoshi N, Xu D, Tajiri K, Feng D, Stujanna EN, Yonebayashi S, Nakagawa Y, Shimano H, Nogami A, Koike A, Aonuma K, Ieda M. Exercise training reduces ventricular arrhythmias through restoring calcium handling and sympathetic tone in myocardial infarction mice. Physiol Rep 2019; 7:e13972. [PMID: 30806037 PMCID: PMC6389758 DOI: 10.14814/phy2.13972] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 12/21/2022] Open
Abstract
Exercise can improve morbidity and mortality in heart failure patients; however, the underlying mechanisms remain to be fully investigated. Thus, we investigated the effects of exercise on cardiac function and ventricular arrhythmias in myocardial infarction (MI) induced heart failure mice. Wild-type male mice underwent sham-operation or permanent left coronary artery ligation to induce MI. MI mice were divided into a sedentary (MI-Sed) and two intervention groups: MI-Ex (underwent 6-week treadmill exercise training) and MI-βb (oral bisoprolol treatment (1 mg/kg/d) without exercise). Cardiac function and structure were assessed by echocardiography and histology. Exercise capacity and cardiopulmonary function was accepted as oxygen consumption at peak exercise (peak VO2 ). Autonomic nervous system function and the incidence of spontaneous ventricular arrhythmia were evaluated via telemetry recording. mRNA and protein expressions in the left ventricle (LV) were investigated by real-time PCR and Western blotting. There were no differences in survival rate, MI size, cardiac function and structure, while exercise training improved peak VO2 . Compared with MI-Sed, MI-Ex, and MI-βb showed decreased sympathetic tone and lower incidence of spontaneous ventricular arrhythmia. By Western blot, the hyperphosphorylation of CaMKII and RyR2 were restored by exercise and β-blocker treatment. Furthermore, elevated expression of miR-1 and decreased expression of its target protein PP2A were recovered by exercise and β-blocker treatment. Continuous intensive exercise training can suppress ventricular arrhythmias in subacute to chronic phase of MI through restoring autonomic imbalance and impaired calcium handling, similarly to that for β-blockers.
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Affiliation(s)
- Rujie Qin
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Nobuyuki Murakoshi
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - DongZhu Xu
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Kazuko Tajiri
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Duo Feng
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Endin N. Stujanna
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Saori Yonebayashi
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism)Faculty of MedicineUniversity of TsukubaTsukubaJapan
| | - Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism)Faculty of MedicineUniversity of TsukubaTsukubaJapan
| | - Akihiko Nogami
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Akira Koike
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
- Medical ScienceFaculty of MedicineUniversity of TsukubaTsukubaJapan
| | - Kazutaka Aonuma
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
| | - Masaki Ieda
- Department of CardiologyFaculty of MedicineGraduate School of Comprehensive Human SciencesUniversity of TsukubaTsukubaJapan
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Lozano-Velasco E, Garcia-Padilla C, Aránega AE, Franco D. Genetics of Atrial Fibrilation: In Search of Novel Therapeutic Targets. Cardiovasc Hematol Disord Drug Targets 2019; 19:183-194. [PMID: 30727926 DOI: 10.2174/1871529x19666190206150349] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic disease in humans, ranging from 2% in the general population and rising up to 10-12% in 80+ years. Genetic analyses of AF familiar cases have identified a series of point mutations in distinct ion channels, supporting a causative link. However, these genetic defects only explain a minority of AF patients. Genomewide association studies identified single nucleotide polymorphisms (SNPs), close to PITX2 on 4q25 chromosome, that are highly associated to AF. Subsequent GWAS studies have identified several new loci, involving additional transcription and growth factors. Furthermore, these risk 4q25 SNPs serve as surrogate biomarkers to identify AF recurrence in distinct surgical and pharmacological interventions. Experimental studies have demonstrated an intricate signalling pathway supporting a key role of the homeobox transcription factor PITX2 as a transcriptional regulator. Furthermore, cardiovascular risk factors such as hyperthyroidism, hypertension and redox homeostasis have been identified to modulate PITX2 driven gene regulatory networks. We provide herein a state-of-the-art review of the genetic bases of atrial fibrillation, our current understanding of the genetic regulatory networks involved in AF and its plausible usage for searching novel therapeutic targets.
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Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia E Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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42
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Li N, Zhou H, Tang Q. miR-133: A Suppressor of Cardiac Remodeling? Front Pharmacol 2018; 9:903. [PMID: 30174600 PMCID: PMC6107689 DOI: 10.3389/fphar.2018.00903] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/23/2018] [Indexed: 01/28/2023] Open
Abstract
Cardiac remodeling, which is characterized by mechanical and electrical remodeling, is a significant pathophysiological process involved in almost all forms of heart diseases. MicroRNAs (miRNAs) are a group of non-coding RNAs of 20–25 nucleotides in length that primarily regulate gene expression by promoting mRNA degradation or post-transcriptional repression in a sequence-specific manner. Three miR-133 genes have been identified in the human genome, miR-133a-1, miR-133a-2, and miR-133b, which are located on chromosomes 18, 20, and 6, respectively. These miRNAs are mainly expressed in muscle tissues and appear to repress the expression of non-muscle genes. Based on accumulating evidence, miR-133 participates in the proliferation, differentiation, survival, hypertrophic growth, and electrical conduction of cardiac cells, which are essential for cardiac fibrosis, cardiac hypertrophy, and arrhythmia. Nevertheless, the roles of miR-133 in cardiac remodeling are ambiguous, and the mechanisms are also sophisticated, involving many target genes and signaling pathways, such as RhoA, MAPK, TGFβ/Smad, and PI3K/Akt. Therefore, in this review, we summarize the critical roles of miR-133 and its potential mechanisms in cardiac remodeling.
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Affiliation(s)
- Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Heng Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Qizhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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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.
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44
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Spinelli V, Sartiani L, Mugelli A, Romanelli MN, Cerbai E. Hyperpolarization-activated cyclic-nucleotide-gated channels: pathophysiological, developmental, and pharmacological insights into their function in cellular excitability. Can J Physiol Pharmacol 2018; 96:977-984. [PMID: 29969572 DOI: 10.1139/cjpp-2018-0115] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both Na+ and K+, blocked by millimolar concentrations of extracellular Cs+ and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, If, in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical If occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular If and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of-function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines.
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Affiliation(s)
- Valentina Spinelli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy
| | - Laura Sartiani
- Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy
| | - Alessandro Mugelli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy
| | - Maria Novella Romanelli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy
| | - Elisabetta Cerbai
- Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy
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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.
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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
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Characterizing the role of atrial natriuretic peptide signaling in the development of embryonic ventricular conduction system. Sci Rep 2018; 8:6939. [PMID: 29720615 PMCID: PMC5932026 DOI: 10.1038/s41598-018-25292-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 04/18/2018] [Indexed: 01/08/2023] Open
Abstract
Patients born with congenital heart defects frequently encounter arrhythmias due to defects in the ventricular conduction system (VCS) development. Although recent studies identified transcriptional networks essential for the heart development, there is scant information on the mechanisms regulating VCS development. Based on the association of atrial natriuretic peptide (ANP) expression with VCS forming regions, it was reasoned that ANP could play a critical role in differentiation of cardiac progenitor cells (CPCs) and cardiomyocytes (CMs) toward a VCS cell lineage. The present study showed that treatment of embryonic ventricular cells with ANP or cell permeable 8-Br-cGMP can induce gene expression of important VCS markers such as hyperpolarization-activated cyclic nucleotide-gated channel-4 (HCN4) and connexin 40 (Cx40). Inhibition of protein kinase G (PKG) via Rp-8-pCPT-cGMPS further confirmed the role of ANP/NPRA/cGMP/PKG pathway in the regulation of HCN4 and Cx40 gene expression. Additional experiments indicated that ANP may regulate VCS marker gene expression by modulating levels of miRNAs that are known to control the stability of transcripts encoding HCN4 and Cx40. Genetic ablation of NPRA revealed significant decreases in VCS marker gene expression and defects in Purkinje fiber arborisation. These results provide mechanistic insights into the role of ANP/NPRA signaling in VCS formation.
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Yu G, Li N, Zhao Y, Wang W, Feng XL. Salidroside induces apoptosis in human ovarian cancer SKOV3 and A2780 cells through the p53 signaling pathway. Oncol Lett 2018; 15:6513-6518. [PMID: 29616120 DOI: 10.3892/ol.2018.8090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 11/16/2017] [Indexed: 12/15/2022] Open
Abstract
Salidroside is one of the most potent compounds extracted from the plant Rhodiola rosea, and its cardiovascular protective effects have been studied extensively. However, the role of salidroside in human ovarian carcinoma remains unknown. The aim of the current study was to investigate the effects of salidroside on the proliferation and apoptosis of SKOV3 and A2780 cells using MTT assay and acridine orange/ethidium bromide staining. Salidroside activated caspase-3 and upregulated the levels of apoptosis-inducing factor, Bcl-2-associated X and Bcl-2-associated death promoter (Bad) proteins. Furthermore, salidroside downregulated the levels of Bcl-2, p-Bad and X-linked inhibitor of apoptosis proteins. Salidroside activated the caspase-dependent pathway in SKOV3 and A2780 cells, upregulating p53, p21Cip1/Waf1 and p16INK4a. These results suggest that the p53/p21Cip1/Waf1/p16INK4a pathway may serve a key function in salidroside-mediated effects on SKOV3 and A2780 cells. The current findings indicate that salidroside may be a promising novel drug candidate for ovarian cancer therapy.
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Affiliation(s)
- Ge Yu
- Department of Gynecology of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Na Li
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Yan Zhao
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Wei Wang
- Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Xiao-Ling Feng
- Department of Gynecology of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China.,Department of Gynecology of Traditional Chinese Medicine, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
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Down-regulation of miR-133a/b in patients with myocardial infarction correlates with the presence of ventricular fibrillation. Biomed Pharmacother 2018; 99:65-71. [PMID: 29324314 DOI: 10.1016/j.biopha.2018.01.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 12/22/2017] [Accepted: 01/03/2018] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of physiologic and pathologic conditions of the heart. Animal models of heart diseases have shown that miRNAs may contribute to the development of arrhythmias. However, little is known about the expression of muscle- and cardiac-specific miRNAs in patients with myocardial infarction (MI) who have developed ventricular fibrillation (VF). Our study included 47 patients who had died from myocardial infarction (MI), 23 with clinically proven VF and 24 without VF. Autopsy samples of infarcted tissue and remote myocardium were available (n = 94). Heart tissue from 8 healthy trauma victims was included as control. Expression of miR-1, miR-133a/b and miR-208 was analyzed using real-time PCR (qPCR). In patients with MI with VF, we observed down-regulation of miR-133a/b, and this down-regulation was even stronger 2-7 days after MI. miR-208 was up-regulated in remote myocardium irrespective of the presence of VF. Deregulation of miR-1 and miR-208 was not related to the presence of VF. Our results suggest that down-regulation of miR-133a/b might contribute to the development of VF in patients with MI. However, up-regulation of miR-1 and miR-208 in remote myocardium might play a role in cardiac remodeling after MI, at least to certain degree.
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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.
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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
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Sartiani L, Mannaioni G, Masi A, Novella Romanelli M, Cerbai E. The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol Rev 2017; 69:354-395. [PMID: 28878030 DOI: 10.1124/pr.117.014035] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 07/07/2017] [Indexed: 12/22/2022] Open
Abstract
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.
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Affiliation(s)
- Laura Sartiani
- Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy
| | - Guido Mannaioni
- Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy
| | - Alessio Masi
- Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy
| | - Maria Novella Romanelli
- Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy
| | - Elisabetta Cerbai
- Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy
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