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1
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Zou E, Xu X, Chen L. Potential of plasma biomarkers for heart failure prediction, management, and prognosis: A multiomics perspective. Heart Fail Rev 2025; 30:55-67. [PMID: 39377997 DOI: 10.1007/s10741-024-10443-5] [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] [Accepted: 09/25/2024] [Indexed: 12/15/2024]
Abstract
Heart failure (HF) remains a major global health challenge, and more effective and comprehensive plasma biomarkers are needed to effectively treat HF patients. Multiomics studies have shown that DNA fragments, noncoding RNAs, proteins, and metabolites may be potential plasma biomarkers for HF. However, comprehensive reviews that focus on research on plasma biomarkers for HF from an omics perspective are lacking. This review summarizes the applications of various omics approaches in the exploration of biomarkers related to the risk assessment, diagnosis, subtype classification, medical management, and prognosis prediction of HF. Moreover, as heart transplantation and left ventricular assistant device (LVAD) implantation are terminal therapies for end-stage HF patients, this review also discusses the role of cell-free DNA as a biomarker for cardiac transplant rejection and omics studies of plasma biomarkers in patients who respond to LVAD therapy. Our findings suggest that future omics research on HF biomarkers should employ integrated multiomics methods and expand the sample size to increase the robustness of the results and that the identified biomarkers should be further validated in large cohorts.
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Affiliation(s)
- Erhou Zou
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinjie Xu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liang Chen
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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2
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Carabetta N, Siracusa C, Leo I, Panuccio G, Strangio A, Sabatino J, Torella D, De Rosa S. Cardiomyopathies: The Role of Non-Coding RNAs. Noncoding RNA 2024; 10:53. [PMID: 39449507 PMCID: PMC11503404 DOI: 10.3390/ncrna10060053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/16/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024] Open
Abstract
Cardiomyopathies are the structural and functional disorders of the myocardium. Etiopathogenesis is complex and involves an interplay of genetic, environmental, and lifestyle factors eventually leading to myocardial abnormalities. It is known that non-coding (Nc) RNAs, including micro (mi)-RNAs and long non-coding (lnc) RNAs, play a crucial role in regulating gene expression. Several studies have explored the role of miRNAs in the development of various pathologies, including heart diseases. In this review, we analyzed various patterns of ncRNAs expressed in the most common cardiomyopathies: dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. Understanding the role of different ncRNAs implicated in cardiomyopathic processes may contribute to the identification of potential therapeutic targets and novel risk stratification models based on gene expression. The analysis of ncRNAs may also be helpful to unveil the molecular mechanisms subtended to these diseases.
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Affiliation(s)
- Nicole Carabetta
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.C.); (C.S.)
| | - Chiara Siracusa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.C.); (C.S.)
| | - Isabella Leo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (I.L.); (G.P.); (A.S.); (J.S.); (D.T.)
| | - Giuseppe Panuccio
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (I.L.); (G.P.); (A.S.); (J.S.); (D.T.)
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité Berlin, 12200 Berlin, Germany
| | - Antonio Strangio
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (I.L.); (G.P.); (A.S.); (J.S.); (D.T.)
| | - Jolanda Sabatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (I.L.); (G.P.); (A.S.); (J.S.); (D.T.)
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (I.L.); (G.P.); (A.S.); (J.S.); (D.T.)
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.C.); (C.S.)
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Vermersch E, Neuvendel S, Jouve C, Ruiz-Velasco A, Pereira C, Seguret M, Cattin-Messaoudi ME, Lotfi S, Dorval T, Berson P, Hulot JS. hsa-miR-548v controls the viscoelastic properties of human cardiomyocytes and improves their relaxation rates. JCI Insight 2024; 9:e161356. [PMID: 38165745 PMCID: PMC11143964 DOI: 10.1172/jci.insight.161356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 12/19/2023] [Indexed: 01/04/2024] Open
Abstract
The impairment of left ventricular (LV) diastolic function with an inadequate increase in myocardial relaxation velocity directly results in lower LV compliance, increased LV filling pressures, and heart failure symptoms. The development of agents facilitating the relaxation of human cardiomyocytes requires a better understanding of the underlying regulatory mechanisms. We performed a high-content microscopy-based screening in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using a library of 2,565 human miRNA mimics and measured relaxation kinetics via high-computing analyses of motion movies. We identified hsa-miR-548v, a primate-specific miRNA, as the miRNA producing the largest increase in relaxation velocities. This positive lusitropic effect was reproduced in engineered cardiac tissues generated with healthy and BRAF T599R mutant hiPSC-CMs and was independent of changes in calcium transients. Consistent with improvements in viscoelastic responses to mechanical stretch, RNA-Seq showed that hsa-miR-548v downregulated multiple targets, especially components of the mechanosensing machinery. The exogenous administration of hsa-miR-548v in hiPSC-CMs notably resulted in a significant reduction of ANKRD1/CARP1 expression and localization at the sarcomeric I-band. This study suggests that the sarcomere I-band is a critical control center regulating the ability of cardiomyocytes to relax and is a target for improving relaxation and diastolic dysfunction.
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Affiliation(s)
- Eva Vermersch
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
- Institut de recherches Servier, In vitro Pharmacology unit, and
| | | | - Charlène Jouve
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
| | | | - Céline Pereira
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
| | - Magali Seguret
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
| | | | - Sofia Lotfi
- Institut de recherches Servier, In vitro Pharmacology unit, and
| | - Thierry Dorval
- Institut de recherches Servier, In vitro Pharmacology unit, and
| | - Pascal Berson
- Institut de recherches Servier, Cardiovascular and Metabolism Therapeutic Area, Croissy-sur-seine, France
| | - Jean-Sébastien Hulot
- Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
- CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, F-75015, Paris, France
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4
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Alexandraki A, Papageorgiou E, Zacharia M, Keramida K, Papakonstantinou A, Cipolla CM, Tsekoura D, Naka K, Mazzocco K, Mauri D, Tsiknakis M, Manikis GC, Marias K, Marcou Y, Kakouri E, Konstantinou I, Daniel M, Galazi M, Kampouroglou E, Ribnikar D, Brown C, Karanasiou G, Antoniades A, Fotiadis D, Filippatos G, Constantinidou A. New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review. Cancers (Basel) 2023; 15:3290. [PMID: 37444400 PMCID: PMC10340234 DOI: 10.3390/cancers15133290] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. AIM To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. METHODS A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013-2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. RESULTS The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. CONCLUSIONS We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.
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Affiliation(s)
- Alexia Alexandraki
- A.G. Leventis Clinical Trials Unit, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (E.P.); (M.Z.)
| | - Elisavet Papageorgiou
- A.G. Leventis Clinical Trials Unit, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (E.P.); (M.Z.)
| | - Marina Zacharia
- A.G. Leventis Clinical Trials Unit, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (E.P.); (M.Z.)
| | - Kalliopi Keramida
- 2nd Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
- Cardiology Department, General Anti-Cancer Oncological Hospital, Agios Savvas, 11522 Athens, Greece
| | - Andri Papakonstantinou
- Department of Oncology-Pathology, Karolinska Institute, 17176 Stockholm, Sweden;
- Department for Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Carlo M. Cipolla
- Cardioncology and Second Opinion Division, European Institute of Oncology (IEO), IRCCS, Via Ripamonti 435, 20141 Milan, Italy;
| | - Dorothea Tsekoura
- 2nd Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, 76 Vas. Sofias Av., 11528 Athens, Greece; (D.T.); (E.K.)
| | - Katerina Naka
- 2nd Cardiology Department, University of Ioannina Medical School, 45110 Ioannina, Greece;
| | - Ketti Mazzocco
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology IRCCS, 20139 Milan, Italy;
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Davide Mauri
- Department of Medical Oncology, University of Ioannina, 45110 Ioannina, Greece;
| | - Manolis Tsiknakis
- Department of Electrical and Computer Engineering, Hellenic Mediterranean University, 71410 Heraklion, Greece; (M.T.); (K.M.)
- Computational BioMedicine Laboratory (CBML), Institute of Computer Science, Foundation for Research and Technology Hellas (FORTH), 70013 Heraklion, Greece;
| | - Georgios C. Manikis
- Computational BioMedicine Laboratory (CBML), Institute of Computer Science, Foundation for Research and Technology Hellas (FORTH), 70013 Heraklion, Greece;
| | - Kostas Marias
- Department of Electrical and Computer Engineering, Hellenic Mediterranean University, 71410 Heraklion, Greece; (M.T.); (K.M.)
- Computational BioMedicine Laboratory (CBML), Institute of Computer Science, Foundation for Research and Technology Hellas (FORTH), 70013 Heraklion, Greece;
| | - Yiola Marcou
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (Y.M.); (E.K.); (I.K.); (M.G.)
| | - Eleni Kakouri
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (Y.M.); (E.K.); (I.K.); (M.G.)
| | - Ifigenia Konstantinou
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (Y.M.); (E.K.); (I.K.); (M.G.)
| | - Maria Daniel
- Department of Radiation Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus;
| | - Myria Galazi
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (Y.M.); (E.K.); (I.K.); (M.G.)
| | - Effrosyni Kampouroglou
- 2nd Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, 76 Vas. Sofias Av., 11528 Athens, Greece; (D.T.); (E.K.)
| | - Domen Ribnikar
- Division of Medical Oncology, Institute of Oncology Ljubljana, Faculty of Medicine, University of Ljubljana, Zaloska Cesta 2, 1000 Ljubljana, Slovenia;
| | - Cameron Brown
- Translational Medicine, Stremble Ventures Ltd., 59 Christaki Kranou, Limassol 4042, Cyprus;
| | - Georgia Karanasiou
- Biomedical Research Institute, Foundation for Research and Technology, Hellas, 45500 Ioannina, Greece;
| | - Athos Antoniades
- Research and Development, Stremble Ventures Ltd., 59 Christaki Kranou, Limassol 4042, Cyprus;
| | - Dimitrios Fotiadis
- Unit of Medical Technology and Intelligent Information Systems, Department of Materials Science and Engineering, University of Ioannina, 45110 Ioannina, Greece;
| | - Gerasimos Filippatos
- Cardio-Oncology Clinic, Heart Failure Unit, Department of Cardiology, National and Kapodistrian University of Athens Medical School, Athens University Hospital Attikon, 11527 Athens, Greece;
| | - Anastasia Constantinidou
- Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Nicosia 2006, Cyprus; (Y.M.); (E.K.); (I.K.); (M.G.)
- School of Medicine, University of Cyprus, Panepistimiou 1, Aglantzia, Nicosia 2408, Cyprus
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Dantas-Komatsu RCS, Cruz MS, Freire PP, Diniz RVZ, Bortolin RH, Cabral-Marques O, Souza KBDS, Hirata MH, Hirata RDC, Reis BZ, Jurisica I, Silbiger VN, Luchessi AD. The let-7b-5p, miR-326, and miR-125a-3p are associated with left ventricular systolic dysfunction in post-myocardial infarction. Front Cardiovasc Med 2023; 10:1151855. [PMID: 37252118 PMCID: PMC10218134 DOI: 10.3389/fcvm.2023.1151855] [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: 01/26/2023] [Accepted: 04/19/2023] [Indexed: 05/31/2023] Open
Abstract
Background Acute ST-elevation myocardial infarction (STEMI) can lead to adverse cardiac remodeling, resulting in left ventricular systolic dysfunction (LVSd) and heart failure. Epigenetic regulators, such as microRNAs, may be involved in the physiopathology of LVSd. Objective This study explored microRNAs in peripheral blood mononuclear cells (PBMC) of post-myocardial infarction patients with LVSd. Methods Post-STEMI patients were grouped as having (LVSd, n = 9) or not LVSd (non-LVSd, n = 16). The expression of 61 microRNAs was analyzed in PBMC by RT-qPCR and the differentially expressed microRNAs were identified. Principal Component Analysis stratified the microRNAs based on the development of dysfunction. Predictive variables of LVSd were investigated through logistic regression analysis. A system biology approach was used to explore the regulatory molecular network of the disease and an enrichment analysis was performed. Results The let-7b-5p (AUC: 0.807; 95% CI: 0.63-0.98; p = 0.013), miR-125a-3p (AUC: 0.800; 95% CI: 0.61-0.99; p = 0.036) and miR-326 (AUC: 0.783; 95% CI: 0.54-1.00; p = 0.028) were upregulated in LVSd (p < 0.05) and discriminated LVSd from non-LVSd. Multivariate logistic regression analysis showed let-7b-5p (OR: 16.00; 95% CI: 1.54-166.05; p = 0.020) and miR-326 (OR: 28.00; 95% CI: 2.42-323.70; p = 0.008) as predictors of LVSd. The enrichment analysis revealed association of the targets of these three microRNAs with immunological response, cell-cell adhesion, and cardiac changes. Conclusion LVSd alters the expression of let-7b-5p, miR-326, and miR-125a-3p in PBMC from post-STEMI, indicating their potential involvement in the cardiac dysfunction physiopathology and highlighting these miRNAs as possible LVSd biomarkers.
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Affiliation(s)
| | - Marina Sampaio Cruz
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Division of Cardiology, Department of Medicine, UC San Diego, San Diego, CA, United States
| | - Paula Paccielli Freire
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rosiane Viana Zuza Diniz
- Department of Clinical Medicine, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Raul Hernandes Bortolin
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil
- Department of Cardiology, Boston Children’s Hospital/Harvard Medical School, Boston, MA, United States
| | - Otávio Cabral-Marques
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil
- Division of Molecular Medicine, Departmentof Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
- Laboratory of Medical Investigation, University of São Paulo School of Medicine, São Paulo, Brazil
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Mario Hiroyuki Hirata
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Rosario Dominguez Crespo Hirata
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Bruna Zavarize Reis
- Department of Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
| | - Igor Jurisica
- Division of Orthopedic Surgery, Schroeder Arthritis Institute and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
- Slovak Academy of Sciences, Institute of Neuroimmunology, Bratislava, Slovakia
| | - Vivian Nogueira Silbiger
- Department of Clinical and Toxicology Analysis, Federal University of Rio Grande do Norte, Natal, Brazil
- Translational Medicine, The Hospital for Sick Children (SickKids), Toronto, ON, Canada
| | - Andre Ducati Luchessi
- Postgraduate Program in Health Sciences, Federal University of Rio Grande do Norte, Natal, Brazil
- Translational Medicine, The Hospital for Sick Children (SickKids), Toronto, ON, Canada
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Witten A, Martens L, Schäfer AC, Troidl C, Pankuweit S, Vlacil AK, Oberoi R, Schieffer B, Grote K, Stoll M, Markus B. Monocyte subpopulation profiling indicates CDK6-derived cell differentiation and identifies subpopulation-specific miRNA expression sets in acute and stable coronary artery disease. Sci Rep 2022; 12:5589. [PMID: 35379829 PMCID: PMC8979987 DOI: 10.1038/s41598-022-08600-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 03/09/2022] [Indexed: 12/20/2022] Open
Abstract
Coronary artery disease (CAD) is a long-lasting inflammatory disease characterized by monocyte migration into the vessel wall leading to clinical events like myocardial infarction (MI). However, the role of monocyte subsets, especially their miRNA-driven differentiation in this scenario is still in its infancy. Here, we characterized monocyte subsets in controls and disease phenotypes of CAD and MI patients using flow cytometry and miRNA and mRNA expression profiling using RNA sequencing. We observed major differences in the miRNA profiles between the classical (CD14++CD16−) and nonclassical (CD14+CD16++) monocyte subsets irrespective of the disease phenotype suggesting the Cyclin-dependent Kinase 6 (CDK6) to be an important player in monocyte maturation. Between control and MI patients, we found a set of miRNAs to be differentially expressed in the nonclassical monocytes and targeting CCND2 (Cyclin D2) that is able to enhance myocardial repair. Interestingly, miRNAs as miR-125b playing a role in vascular calcification were differentially expressed in the classical subset in patients suffering from CAD and not MI in comparison to control samples. In conclusion, our study describes specific peculiarities of monocyte subset miRNA expression in control and diseased samples and provides basis to further functional analysis and to identify new cardiovascular disease treatment targets.
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7
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Chen X, Li Q, Zhang Z, Yang M, Wang E. Identification of Potential Diagnostic Biomarkers From Circulating Cells During the Course of Sleep Deprivation-Related Myocardial Infarction Based on Bioinformatics Analyses. Front Cardiovasc Med 2022; 9:843426. [PMID: 35369343 PMCID: PMC8969017 DOI: 10.3389/fcvm.2022.843426] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 02/22/2022] [Indexed: 01/01/2023] Open
Abstract
Background Myocardial infarction (MI) is the leading cause of death from non-infectious diseases worldwide and results in rapid deterioration due to the sudden rupture of plaques associated with atherosclerosis, a chronic inflammatory disease. Sleep is a key factor that regulates immune homeostasis of the body. The imbalance in circulating immune cells caused by sleep deprivation (SD) may represent a risk factor leading to the rapid deterioration of plaques and MI. Therefore, it is of profound significance to identify diagnostic biomarkers for preventing SD-related MI. Methods In the present study, we identified coexpressed differentially expressed genes (co-DEGs) between peripheral blood mononuclear cells from MI and SD samples (compared to controls) from a public database. LASSO regression analysis was applied to identify significant diagnostic biomarkers from co-DEGs. Moreover, receiver operating characteristic (ROC) curve analysis was performed to test biomarker accuracy and diagnostic ability. We further analyzed immune cell enrichment in MI and SD samples using the CIBERSORT algorithm, and the correlation between biomarkers and immune cell composition was assessed. We also investigated whether diagnostic biomarkers are involved in immune cell signaling pathways in SD-related MI processes. Results A total of 10 downregulated co-DEGs from the sets of MI-DEGs and SD-DEGs were overlapped. After applying LASSO regression analysis, SYTL2, KLRD1, and C12orf75 were selected and validated as diagnostic biomarkers using ROC analysis. Next, we found that resting NK cells were downregulated in both the MI samples and SD samples, which is similar to the changes noted for SYTL2. Importantly, SYTL2 was strongly positively correlated not only with resting NK cells but also with most genes related to NK cell markers in the MI and SD datasets. Moreover, SYTL2 was highly associated with genes in NK cell signaling pathways, including the MAPK signaling pathway, cytotoxic granule movement and exocytosis, and NK cell activation. Furthermore, GSEA and KEGG analyses provided evidence that the DEGs identified from MI samples with low vs. high SYTL2 expression exhibited a strong association with the regulation of the immune response and NK cell-mediated cytotoxicity. Conclusion In conclusion, SYTL2, KLRD1, and C12orf75 represent potential diagnostic biomarkers of MI. The association between SYTL2 and resting NK cells may be critically involved in SD-related MI development and occurrence.
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Affiliation(s)
- Xiang Chen
- Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Xiangya Hospital Central South University, Changsha, China
| | - Qian Li
- Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, China
| | - Zhong Zhang
- Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, China
| | - Minjing Yang
- Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, China
| | - E. Wang
- Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Xiangya Hospital Central South University, Changsha, China
- *Correspondence: E. Wang
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8
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Chiti E, Di Paolo M, Turillazzi E, Rocchi A. MicroRNAs in Hypertrophic, Arrhythmogenic and Dilated Cardiomyopathy. Diagnostics (Basel) 2021; 11:diagnostics11091720. [PMID: 34574061 PMCID: PMC8469137 DOI: 10.3390/diagnostics11091720] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs of about 20 nucleotides in length, involved in the regulation of many biochemical pathways in the human body. The level of miRNAs in tissues and circulation can be deregulated because of altered pathophysiological mechanisms; thus, they can be employed as biomarkers for different pathological conditions, such as cardiac diseases. This review summarizes published findings of these molecular biomarkers in the three most common structural cardiomyopathies: human dilated, arrhythmogenic and hypertrophic cardiomyopathy.
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Affiliation(s)
- Enrica Chiti
- Institute of Life Science, Scuola Superiore Sant’Anna, 56124 Pisa, Italy;
| | - Marco Di Paolo
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Emanuela Turillazzi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
| | - Anna Rocchi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (M.D.P.); (E.T.)
- Correspondence:
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Bastami M, Mahmoodzadeh H, Saadatian Z, Daraei A, Zununi Vahed S, Mansoori Y, Nariman-Saleh-Fam Z. Perturbation of miR-146b and relevant inflammatory elements in esophageal carcinoma patients supports an immune downregulatory mechanism. Pathol Res Pract 2021; 225:153560. [PMID: 34311393 DOI: 10.1016/j.prp.2021.153560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/10/2021] [Accepted: 07/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Esophageal Cancer is known as one of the deadliest cancers worldwide with the squamous cell carcinoma (ESCC) being the predominant subtype. There is a growing body of evidence linking the dysregulated microRNA (miRNA) pathway of immune cells to the progression of several tumors. In a previous study, we investigated molecular alterations pertaining to miR-146a and some components of NF-kB signaling pathway and proposed a possible immune downregulatory mechanism in peripheral blood mononuclear cells (PBMCs) of ESCC patients. Here, we further scrutinized other components of this pathway by evaluating PBMC levels of miR-146b, TLR4, IL10, and TNFA. METHODS Gene expressions were quantified using RT-qPCR assays. To prevent the vulnerability of results to the expression instability of reference genes, nine additional transcripts were quantified, and stable reference genes for normalizing qPCR data were identified using the NormFinder and the geNorm algorithms. The efficiency-corrected normalized relative quantity values were used to compare gene expressions among study groups. RESULTS The PBMC expression of miR-146b and TNFA was downregulated in ESCC patients as compared to healthy subjects. While the level of TLR4 was not different among the study groups, the PBMC level of IL10 was upregulated in ESCC patients. Logistic regression analyses coupled with the ROC curve and cross-validation analysis suggested that PBMC expression may serve as potential candidate biomarker for discriminating ESCC patients from healthy subjects. CONCLUSION The present findings, in line with our previous report, propose a particular gene expression pattern in PBMCs of ESCC patients, providing evidence in support of an immune downregulatory mechanism.
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Affiliation(s)
- Milad Bastami
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Zahra Saadatian
- Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abdolreza Daraei
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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10
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Maheronnaghsh M, Niktab I, Enayati S, Amoli MM, Hosseini SK, Tavakkoly-Bazzaz J. Differentially expressed miR-152, a potential biomarker for in-stent restenosis (ISR) in peripheral blood mononuclear cells (PBMCs) of coronary artery disease (CAD) patients. Nutr Metab Cardiovasc Dis 2021; 31:1137-1147. [PMID: 33712363 DOI: 10.1016/j.numecd.2020.09.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS In-stent restenosis (ISR) remains the most daunting challenge of current treatments of coronary artery disease (CAD). MicroRNAs (miRNAs) are prominent regulators of key pathological processes leading to restenosis and used as diagnostic tools in different studies. miR-152 and miR-148a are implicated to contribute in the putative intracellular mechanisms of ISR. The aim of present study is to investigate the potential early-stage diagnostic role of miR-152 and miR-148a expression levels for ISR in peripheral blood mononuclear cells (PBMCs) of patients who underwent stent implantation. METHODS AND RESULTS The miRNAs that are supposed to be involved in the ISR were nominated by bioinformatics approach mainly using miRWalk3. Then by quantitative real-time PCR, we determined the relative expression of miR-152 and miR-148a of PBMCs from ISR patients with their age/sex-matched controls. RESULTS The presence of ISR significantly coincided with a decrease in the relative expression of miR-152. The area under the curve (AUC) for miR-152 receiver operating characteristic (ROC) curve was 0.717 (95% CI; 0.60-0.83) with a sensitivity of 70% and a specificity of 67%, suggesting that the miRNA expression level might be employed to identify patients at risk of ISR. CONCLUSIONS To the best of our knowledge, this is the first work to show that the miR-152 expression level can possibly be applied to predict CAD patients at risk of ISR. The results suggest that the expression levels of miR-152 in PBMCs may serve as a biomarker for ISR. Our finding suggests the importance of miRNA levels in PBMCs as a novel biological tool to detect diseases in their early clinical stages.
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Affiliation(s)
- M Maheronnaghsh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - I Niktab
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - S Enayati
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - M M Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - S K Hosseini
- Department of Cardiovascular Disorders, Division of Interventional Cardiology, Tehran University of Medical Sciences, Tehran, Iran.
| | - J Tavakkoly-Bazzaz
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Bilchick K, Kothari H, Narayan A, Garmey J, Omar A, Capaldo B, McNamara C. Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure. Cardiovasc Res 2021; 116:1311-1322. [PMID: 31612215 DOI: 10.1093/cvr/cvz232] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 08/02/2019] [Accepted: 09/06/2019] [Indexed: 12/17/2022] Open
Abstract
AIMS In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure. METHODS AND RESULTS We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5 years, interquartile range 63.0-66.8 years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1β pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1β (1.80-fold decrease, P = 0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P = 0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P = 0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P = 0.03), and suppression was greater in responders vs. non-responders (P = 0.03 for IL-1β, P = 0.02 for FOS, P = 0.02 for DUSP1, and P = 0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P = 0.002; 2.60-fold higher, DUSP1, P = 0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P = 0.04) and DUSP1 (P = 0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P = 0.008). CONCLUSION Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.
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Affiliation(s)
- Kenneth Bilchick
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - Hema Kothari
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - Aditya Narayan
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - James Garmey
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - Abdullah Omar
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - Brian Capaldo
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
| | - Coleen McNamara
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA, USA
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12
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Gholaminejad A, Zare N, Dana N, Shafie D, Mani A, Javanmard SH. A meta-analysis of microRNA expression profiling studies in heart failure. Heart Fail Rev 2021; 26:997-1021. [PMID: 33443726 DOI: 10.1007/s10741-020-10071-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 12/20/2022]
Abstract
Heart failure (HF) is a major consequence of many cardiovascular diseases with high rate of morbidity and mortality. Early diagnosis and prevention are hampered by the lack of informative biomarkers. The aim of this study was to perform a meta-analysis of the miRNA expression profiling studies in HF to identify novel candidate biomarkers or/and therapeutic targets. A comprehensive literature search of the PubMed for miRNA expression studies related to HF was carried out. The vote counting and robust rank aggregation meta-analysis methods were used to identify significant meta-signatures of HF-miRs. The targets of HF-miRs were identified, and network construction and gene set enrichment analysis (GSEA) were performed to identify the genes and cognitive pathways most affected by the dysregulation of the miRNAs. The literature search identified forty-five miRNA expression studies related to CHF. Shared meta-signature was identified for 3 up-regulated (miR-21, miR-214, and miR-27b) and 13 down-regulated (miR-133a, miR-29a, miR-29b, miR-451, miR-185, miR-133b, miR-30e, miR-30b, miR-1, miR-150, miR-486, miR-149, and miR-16-5p) miRNAs. Network properties showed miR-29a, miR-21, miR-29b, miR-1, miR-16, miR-133a, and miR-133b have the most degree centrality. GESA identified functionally related sets of genes in signaling and community pathways in HF that are the targets of HF-miRs. The miRNA expression meta-analysis identified sixteen highly significant HF-miRs that are differentially expressed in HF. Further validation in large patient cohorts is required to confirm the significance of these miRs as HF biomarkers and therapeutic targets.
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Affiliation(s)
- Alieh Gholaminejad
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasrin Zare
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran
| | - Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran
| | - Davood Shafie
- Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arya Mani
- Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran. .,Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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13
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Rosch S, Rommel KP, Scholz M, Thiele H, Lurz P. Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives. Card Fail Rev 2020; 6:e24. [PMID: 33042584 PMCID: PMC7539142 DOI: 10.15420/cfr.2019.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and has a higher prevalence compared with heart failure with reduced ejection fraction. So far, no effective treatment of HFpEF is available, due to its complex underlying pathophysiology and clinical heterogeneity. This article aims to provide an overview and a future perspective of transcriptomic biomarker research in HFpEF. Detailed characterisation of the HFpEF phenotype and its underlying molecular pathomechanisms may open new perspectives regarding early diagnosis, improved prognostication, new therapeutic targets and tailored therapies accounting for patient heterogeneity, which may improve quality of life. A combination of cross-sectional and longitudinal study designs with sufficiently large sample sizes are required to support this concept.
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Affiliation(s)
- Sebastian Rosch
- Department of Cardiology, Heart Center Leipzig at University of Leipzig Leipzig, Germany
| | - Karl-Philipp Rommel
- Department of Cardiology, Heart Center Leipzig at University of Leipzig Leipzig, Germany
| | - Markus Scholz
- Institute of Medical Informatics, Statistics and Epidemiology, Leipzig University Leipzig, Germany.,Leipzig Research Center for Civilization Diseases (LIFE), Leipzig University Leipzig, Germany
| | - Holger Thiele
- Department of Cardiology, Heart Center Leipzig at University of Leipzig Leipzig, Germany
| | - Philipp Lurz
- Department of Cardiology, Heart Center Leipzig at University of Leipzig Leipzig, Germany
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14
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Nariman-Saleh-Fam Z, Mansoori Y, Saadatian Z, Tavakkoly-Bazzaz J, Daraei A, Zununi Vahed S, Mahmoodzadeh H, Bastami M. Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients. Immunol Invest 2020; 51:290-300. [DOI: 10.1080/08820139.2020.1828454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Ziba Nariman-Saleh-Fam
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Zahra Saadatian
- Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Javad Tavakkoly-Bazzaz
- Medical Genetics Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolreza Daraei
- Department of Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Habibollah Mahmoodzadeh
- Cancer Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Milad Bastami
- Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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Abstract
Heart failure (HF) remains a major cause of death and disability worldwide. Currently, B-type natriuretic peptide and N-terminal pro-brain natriuretic peptide are diagnostic biomarkers used in HF. Although very sensitive, they are not specific enough and do not allow the prediction or early diagnosis of HF. Many ongoing studies focus on determining the underlying cause and understanding the mechanisms of HF on the cellular level. MicroRNAs (miRNAs) are non-coding RNAs which control the majority of cellular processes and therefore are considered to have a potential clinical application in HF. In this review, we aim to provide synthesized information about miRNAs associated with ejection fraction, HF etiology, diagnosis, and prognosis, as well as outline therapeutic application of miRNAs in HF. Further, we discuss methodological challenges associated with the analysis of miRNAs and provide recommendations for defining a study population, collecting blood samples, and selecting detection methods to study miRNAs in a reliable and reproducible way. This review is intended to be an accessible tool for clinicians interested in the field of miRNAs and HF.
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16
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Sun S, Li L, Dong L, Cheng J, Zhao C, Bao C, Wang H. Circulating mRNA and microRNA profiling analysis in patients with ischemic stroke. Mol Med Rep 2020; 22:792-802. [PMID: 32626985 PMCID: PMC7339759 DOI: 10.3892/mmr.2020.11143] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 12/03/2019] [Indexed: 12/15/2022] Open
Abstract
To provide insight into molecular diagnosis and individualized treatment of ischemic stroke (IS), several available datasets in IS were analyzed to identify the differentially expressed genes and microRNAs (miRNAs). Series matrix files from GSE22255 and GSE16561 (mRNA profiles), a well as GSE110993 (miRNA profile) were downloaded from the Gene Expression Omnibus database. System-level clustering was performed with GeneCluster 3.0 software, and gene annotation and pathway enrichment were performed with gene ontology analysis and Database for Annotation, Visualization and Integrated Discovery software. For a protein-protein interaction (PPI) network, Biological General Repository for Interaction Datasets and IntAct interaction information were integrated to determine the interaction of differentially expressed genes. The selected miRNA candidates were imported into the TargetScan, miRDB and miRecords databases for the prediction of target genes. The present study identified 128 upregulated and 231 downregulated genes in female stroke patients, and 604 upregulated and 337 downregulated genes in male stroke patients compared with sex- and age-matched controls. The construction of a PPI network demonstrated that male stroke patients exhibited YWHAE, CUL3 and JUN as network center nodes, and in female patients CYLD, FOS and PIK3R1 interactions were the strongest. Notably, these interactions are mainly involved in immune inflammatory response, apoptosis and other biological pathways, such as blood coagulation. Female and male upregulated genes were cross-validated with another set of Illumina HumanRef-8 v3.0 expression beadchip (GSE16561). Functional item association networks, gene function networks and transcriptional regulatory networks were successfully constructed, and the relationships between miRNAs and target genes were successfully predicted. The present study identified a number of transcription factors, including DEFA1, PDK4, SDPR, TCN1 and MMP9, and miRNAs, including miRNA (miR)-21, miR-143/145, miR-125-5p and miR-122, which may serve important roles in the development of cerebral stroke and may be important molecular indicators for the treatment of IS.
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Affiliation(s)
- Sujuan Sun
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Litao Li
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Lipeng Dong
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Jinming Cheng
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Congying Zhao
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Chu Bao
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
| | - Hebo Wang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei 050050, P.R. China
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17
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Berezin AE, Berezin AA. Extracellular Endothelial Cell-Derived Vesicles: Emerging Role in Cardiac and Vascular Remodeling in Heart Failure. Front Cardiovasc Med 2020; 7:47. [PMID: 32351973 PMCID: PMC7174683 DOI: 10.3389/fcvm.2020.00047] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Extracellular vesicles play a pivotal role in numerous physiological (immune response, cell-to-cell cooperation, angiogenesis) and pathological (reparation, inflammation, thrombosis/coagulation, atherosclerosis, endothelial dysfunction) processes. The development of heart failure is strongly associated with endothelial dysfunction, microvascular inflammation, alteration in tissue repair, and cardiac and vascular remodeling. It has been postulated that activated endothelial cell-derived vesicles are not just transfer forms of several active molecules (such as regulatory peptides, coagulation factors, growth factors, active molecules, hormones that are embedded onto angiogenesis, tissue reparation, proliferation, and even prevention from ischemia/hypoxia), but are instead involved in direct myocardial and vascular damage due to regulation of epigenetic responses of the tissue. These responses are controlled by several factors, such as micro-RNAs, that are transferred inside extracellular vesicles from mother cells to acceptor cells and are transductors of epigenetic signals. Finally, it is not a uniform opinion whether different phenotypes of heart failure are the result of altered cardiac and vascular reparation due to certain epigenetic responses, which are yielded by co-morbidities, such as diabetes mellitus and obesity. The aim of the review is to summarize knowledge regarding the role of various types of extracellular endothelial cell-derived vesicles in the regulation of cardiac and vascular remodeling in heart failure.
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Affiliation(s)
- Alexander E Berezin
- Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye, Ukraine
| | - Alexander A Berezin
- Internal Medicine Department, Medical Academy of Post-graduate Education, Ministry of Health of Ukraine, Zaporozhye, Ukraine
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18
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Calderon-Dominguez M, Belmonte T, Quezada-Feijoo M, Ramos-Sánchez M, Fernández-Armenta J, Pérez-Navarro A, Cesar S, Peña-Peña L, Vea À, Llorente-Cortés V, Mangas A, de Gonzalo-Calvo D, Toro R. Emerging role of microRNAs in dilated cardiomyopathy: evidence regarding etiology. Transl Res 2020; 215:86-101. [PMID: 31505160 DOI: 10.1016/j.trsl.2019.08.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/19/2019] [Accepted: 08/20/2019] [Indexed: 02/08/2023]
Abstract
Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease. This cardiac disorder is a major health problem due to its high prevalence, morbidity, and mortality. DCM is a complex disease with a common phenotype but heterogeneous pathological mechanisms. Early etiological diagnosis and prognosis stratification is crucial for the clinical management of the patient. Advances in imaging technology and genetic tests have provided useful tools for clinical practice. Nevertheless, the assessment of the disease remains challenging. Novel noninvasive indicators are still needed to assist in decision-making. microRNAs (miRNAs), a group of small noncoding RNAs, have been identified as key mediators of cell biology. They are found in a stable form in body fluids and their concentration is altered in response to stress. Previous research has suggested that the miRNA signature constitutes a novel source of noninvasive biomarkers for a wide array of cardiovascular diseases. Specifically, several studies have reported the potential role of miRNAs as clinical indicators among the etiologies of DCM. However, this field has not been reviewed in detail. Here, we summarize the evidence of intracellular and circulating miRNAs in DCM and their usefulness in the development of novel diagnostic, prognostic and therapeutic approaches, with a focus on DCM etiology. Although the findings are still preliminary, due to methodological and technical limitations and the lack of robust population-based studies, miRNAs constitute a promising tool to assist in the clinical management of DCM.
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Affiliation(s)
- Maria Calderon-Dominguez
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain
| | - Thalía Belmonte
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain
| | - Maribel Quezada-Feijoo
- Department of Cardiology, Cruz Roja Central Hospital, Madrid, Spain; Alfonso X University (UAX), Madrid, Spain
| | - Monica Ramos-Sánchez
- Department of Cardiology, Cruz Roja Central Hospital, Madrid, Spain; Alfonso X University (UAX), Madrid, Spain
| | - Juan Fernández-Armenta
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain; Department of Cardiology, Puerta del Mar Universitary Hospital, Cádiz, Spain
| | - Amparo Pérez-Navarro
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain
| | - Sergi Cesar
- Department of Pediatric Cardiology, Sant Joan de Déu Hospital, Barcelona, Spain
| | - Luisa Peña-Peña
- Department of Cardiology, Virgen del Rocio Universitary Hospital, Sevilla, Spain
| | - Àngela Vea
- Institute of Biomedical Research of Barcelona (IIBB) - Spanish National Research Council (CSIC), Barcelona, Spain
| | - Vicenta Llorente-Cortés
- Institute of Biomedical Research of Barcelona (IIBB) - Spanish National Research Council (CSIC), Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; CIBERCV, Institute of Health Carlos III, Madrid, Spain
| | - Alipio Mangas
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain; Department of Internal Medicine, Puerta del Mar Universitary Hospital, Cádiz, Spain; Department of Medicine, School of Medicine, University of Cádiz, Cádiz, Spain
| | - David de Gonzalo-Calvo
- Institute of Biomedical Research of Barcelona (IIBB) - Spanish National Research Council (CSIC), Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; CIBERCV, Institute of Health Carlos III, Madrid, Spain.
| | - Rocio Toro
- Research Unit, Biomedical Research and Innovation Institute of Cádiz (INiBICA), Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain; Department of Internal Medicine, Puerta del Mar Universitary Hospital, Cádiz, Spain; Department of Medicine, School of Medicine, University of Cádiz, Cádiz, Spain.
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19
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Mziaut H, Henniger G, Ganss K, Hempel S, Wolk S, McChord J, Chowdhury K, Ravassard P, Knoch KP, Krautz C, Weitz J, Grützmann R, Pilarsky C, Solimena M, Kersting S. MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling. Mol Metab 2019; 31:150-162. [PMID: 31918917 PMCID: PMC6928290 DOI: 10.1016/j.molmet.2019.11.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/09/2019] [Accepted: 11/15/2019] [Indexed: 12/16/2022] Open
Abstract
Objective MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice. Methods RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132−/− and control mice. Results Partial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212−/− mice than the control littermates. Conclusions This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.
miR-132 is induced in mouse islets upon partial pancreatectomy. miR-132 promotes regeneration of β-cells in vivo following partial pancreatectomy. miR-132 fosters in vitro proliferation/survival through Pten/Akt/Foxo3 signaling. Downstream targets of miR-132 were identified in pancreatic β-cells. miR-132−/− mice have impaired β-cell proliferation.
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Affiliation(s)
- Hassan Mziaut
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Georg Henniger
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Katharina Ganss
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Sebastian Hempel
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Steffen Wolk
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Johanna McChord
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Kamal Chowdhury
- Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
| | - Philippe Ravassard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France
| | - Klaus-Peter Knoch
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Christian Krautz
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | - Jürgen Weitz
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Robert Grützmann
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | | | - Michele Solimena
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Stephan Kersting
- Department of Surgery, University of Erlangen, Erlangen, Germany.
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Saadatian Z, Nariman-Saleh-Fam Z, Bastami M, Mansoori Y, Khaheshi I, Parsa SA, Daraei A, Vahed SZ, Yousefi B, Kafil HS, Eyvazi S, Ghaderian SMH, Omrani MD. Dysregulated expression of STAT1, miR-150, and miR-223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis. J Cell Biochem 2019; 120:19810-19824. [PMID: 31318097 DOI: 10.1002/jcb.29286] [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: 11/16/2018] [Accepted: 02/07/2019] [Indexed: 12/12/2022]
Abstract
Coronary artery disease (CAD) is a multicellular disease characterized by chronic inflammation. Peripheral blood-mononuclear cells (PBMCs), as a critical component of immune system, actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in perturbed PBMC expression. STAT1 is believed to be relevant to CAD pathogenesis through regulating key inflammatory processes and modulating STAT1 expression play key roles in fine-tuning CAD-related inflammatory processes. This study evaluated PBMC expressions of STAT1, and its regulators (miR-150 and miR-223) in a cohort including 72 patients with CAD with significant ( ≥ 50%) stenosis, 30 patients with insignificant ( < 50%) coronary stenosis (ICAD), and 74 healthy controls, and assessed potential of PBMC expressions to discriminate between patients and controls. We designed quantitative real-time polymerase chain reaction (RT-qPCR) assays and identified stable reference genes for normalizing PBMC quantities of miR-150, miR-223, and STAT1 applying geNorm algorithm to six small RNAs and five mRNAs. There was no significant difference between CAD and ICAD patients regarding STAT1 expression. However, both groups of patients had higher levels of STAT1 than healthy controls. miR-150 and miR-223 were differently expressed across three groups of subjects and were downregulated in patients compared with healthy controls, with the lowest expression levels being observed in patients with ICAD. ROC curves suggested that PBMC expressions may separate between different groups of study subjects. PBMC expressions also discriminated different clinical manifestations of CAD from ICADs or healthy controls. In conclusion, the present study reported PBMC dysregulations of STAT1, miR-150, and miR-223, in patients with significant or insignificant coronary stenosis and suggested that these changes may have diagnostic implications.
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Affiliation(s)
- Zahra Saadatian
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ziba Nariman-Saleh-Fam
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yasser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Isa Khaheshi
- Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Alipour Parsa
- Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolreza Daraei
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | | | - Bahman Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Eyvazi
- Department of Biotechnology, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mir Davood Omrani
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
OBJECTIVES The goal of this study was to investigate genes associated with essential hypertension from a system perspective, making use of bioinformatic tools to gain insights that are not evident when focusing at a detail-based resolution. METHODS Using various databases (pathways, Genome Wide Association Studies, knockouts etc.), we compiled a set of about 200 genes that play a major role in hypertension and identified the interactions between them. This enabled us to create a protein-protein interaction network graph, from which we identified key elements, based on graph centrality analysis. Enriched gene regulatory elements (transcription factors and microRNAs) were extracted by motif finding techniques and knowledge-based tools. RESULTS We found that the network is composed of modules associated with functions such as water retention, endothelial vasoconstriction, sympathetic activity and others. We identified the transcription factor SP1 and the two microRNAs miR27 (a and b) and miR548c-3p that seem to play a major role in regulating the network as they exert their control over several modules and are not restricted to specific functions. We also noticed that genes involved in metabolic diseases (e.g. insulin) are central to the network. CONCLUSION We view the blood-pressure regulation mechanism as a system-of-systems, composed of several contributing subsystems and pathways rather than a single module. The system is regulated by distributed elements. Understanding this mode of action can lead to a more precise treatment and drug target discovery. Our analysis suggests that insulin plays a primary role in hypertension, highlighting the tight link between essential hypertension and diseases associated with the metabolic syndrome.
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Nariman-saleh-fam Z, Vahed SZ, Aghaee-Bakhtiari SH, Daraei A, Saadatian Z, Kafil HS, Yousefi B, Eyvazi S, Khaheshi I, Parsa SA, Moravej A, Mousavi N, Bastami M, Mansoori Y. Expression pattern of miR-21, miR-25 and PTEN in peripheral blood mononuclear cells of patients with significant or insignificant coronary stenosis. Gene 2019; 698:170-178. [DOI: 10.1016/j.gene.2019.02.074] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 02/10/2019] [Accepted: 02/22/2019] [Indexed: 12/12/2022]
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micro-RNAs dependent regulation of DNMT and HIF1α gene expression in thrombotic disorders. Sci Rep 2019; 9:4815. [PMID: 30894555 PMCID: PMC6426883 DOI: 10.1038/s41598-018-38057-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 11/21/2018] [Indexed: 01/25/2023] Open
Abstract
MicroRNAs (miRNAs) are involved in a wide variety of cellular processes and post-transcriptionally regulate several mechanism and diseases. However, contribution of miRNAs functioning during hypoxia and DNA methylation together is less understood. The current study was aimed to find a shared miRNAs signature upstream to hypoxia (via HIF gene family members) and methylation (via DNMT gene family members). This was followed by the global validation of the hypoxia related miRNA signature using miRNA microarray meta-analysis of the hypoxia induced human samples. We further concluded the study by looking into thrombosis related terms and pathways enriched during protein-protein interaction (PPI) network analysis of these two sets of gene family. Network prioritization of these shared miRNAs reveals miR-129, miR-19band miR-23b as top regulatory miRNAs. A comprehensive meta-analysis of microarray datasets of hypoxia samples revealed 29 differentially expressed miRNAs. GSEA of the interacting genes in the DNMT-HIF PPI network indicated thrombosis associated pathways including “Hemostasis”, “TPO signaling pathway” and “angiogenesis”. Interestingly, the study has generated a novel database of candidate miRNA signatures shared between hypoxia and methylation, and their relation to thrombotic pathways, which might aid in the development of potential therapeutic biomarkers.
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Yao G, Niu W, Zhu X, He M, Kong L, Chen S, Zhang L, Cheng Z. hsa_circRNA_104597: a novel potential diagnostic and therapeutic biomarker for schizophrenia. Biomark Med 2019; 13:331-340. [PMID: 30781971 DOI: 10.2217/bmm-2018-0447] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Aim: To assess whether expression of circular RNAs (circRNAs) in peripheral blood mononuclear cells can serve as a biomarker for diagnosis and/or therapeutic response in people living with schizophrenia (SZ). Materials & methods: Differentially expressed circRNAs were screened via microarray in nine individuals living with SZ and nine healthy controls, then quantified using real-time quantitative reverse transcription PCR in SZ (n = 102) and healthy control (n = 103) groups. CircRNAs were re-assessed twice in 30 randomly selected individuals living with SZ after 4- and 8-week antipsychotic treatments. Results: Five circRNAs were differentially expressed between groups. Only hsa_circRNA_104597, which was downregulated in the SZ group, was significantly upregulated after 8-week treatment. Conclusion: Dysregulation of hsa_circRNA_104597 may serve as a novel potential diagnostic and therapeutic biomarker for SZ.
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Affiliation(s)
- Gaofeng Yao
- Department of Psychology, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi, PR China.,Prevention & Treatment Center for Psychological Diseases, No. 904 Hospital of the Chinese People's Liberation Army, Changzhou, PR China
| | - Wei Niu
- Department of Rehabilitation, No. 904 Hospital of Chinese People's Liberation Army, Changzhou, PR China
| | - Xiaoli Zhu
- Prevention & Treatment Center for Psychological Diseases, No. 904 Hospital of the Chinese People's Liberation Army, Changzhou, PR China
| | - Mingjun He
- Prevention & Treatment Center for Psychological Diseases, No. 904 Hospital of the Chinese People's Liberation Army, Changzhou, PR China
| | - Lingming Kong
- Prevention & Treatment Center for Psychological Diseases, No. 904 Hospital of the Chinese People's Liberation Army, Changzhou, PR China
| | - Shengdong Chen
- Department of Neurology, No. 904 Hospital of Chinese People's Liberation Army, Changzhou, PR China
| | - Liyi Zhang
- Prevention & Treatment Center for Psychological Diseases, No. 904 Hospital of the Chinese People's Liberation Army, Changzhou, PR China
| | - Zaohuo Cheng
- Department of Psychology, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi, PR China
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Zhang X, Nie X, Yuan S, Li H, Fan J, Li C, Sun Y, Zhao Y, Hou H, Wang DW, Chen C. Circulating Long Non-coding RNA ENST00000507296 Is a Prognostic Indicator in Patients with Dilated Cardiomyopathy. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 16:82-90. [PMID: 30852379 PMCID: PMC6409414 DOI: 10.1016/j.omtn.2019.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 02/06/2019] [Accepted: 02/06/2019] [Indexed: 12/30/2022]
Abstract
Background: Long non-coding RNAs (lncRNAs) participate in the pathogenesis of cardiovascular diseases. However, whether circulating lncRNAs serve as dilated cardiomyopathy (DCM) biomarkers remains unclear. Methods: Totally, 266 controls and 818 patients were enrolled. First, microarray-based circulating lncRNA profiling was performed in 10 normal controls and 10 patients with DCM. Second, the top 20 differentially expressed lncRNAs were validated by real-time qPCR in 64 controls and 64 DCM patients. Moreover, lncRNA sequencing was performed in three human heart-derived cell types, and the correlation between circulating lncRNA levels and the severity of heart failure was evaluated in the validated population. The validated two lncRNAs were assessed in 198 DCM patients and 198 matched controls. Finally, the sensitivity and specificity of circulating lncRNA expression in DCM diagnosis were evaluated using receiver-operating characteristic curve analysis, while Cox regression and Kaplan-Meier curve analysis were further performed in 552 DCM patients. Results: Eight candidate lncRNA biomarkers were obtained after microarray screening and real-time PCR validation. Among them, five were validated in the second cohort. However, only the levels of circulating lncRNA ENST00000507296 and ENST00000532365 were significantly correlated with the cardiac function, as well as detectable in at least one of the human heart-derived cell types by lncRNA-seq. Importantly, low circulating ENST00000507296 level was associated with high event-free survival in patients with DCM. Conclusions: Circulating lncRNA ENST00000507296 was a prognostic biomarker in patients with DCM.
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Affiliation(s)
- Xudong Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Yuan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Chenze Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Sun
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Yanru Zhao
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Huiying Hou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China.
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China.
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Gupta A, Sugadev R, Sharma YK, Yahmad Y, Khurana P. Role of miRNAs in hypoxia-related disorders. J Biosci 2018; 43:739-749. [PMID: 30207319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Hypoxia is a complex pathophysiological condition. The physiological and molecular responses to this stress have been extensively studied. However, the management of its ill effects still poses a challenge to clinicians. MicroRNAs (miRNAs) are short non-coding RNA molecules that control post-transcriptional gene expression. The regulatory role of miRNAs in hypoxic environments has been studied in many hypoxia-related disorders, however a comprehensive compilation and analysis of all data and the significance of miRNAs in hypoxia adaption is still lacking. This review summarizes the miRNAs related to various hypoxia-related disorders and highlights the computational approaches to study them. This would help in designing novel strategies toward efficient management of hypoxia-related disorders.
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Affiliation(s)
- A Gupta
- Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R and D Organization (DRDO), Timarpur, Delhi 110 054, India
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Gupta A, Sugadev R, Sharma YK, Ahmad Y, Khurana P. Role of miRNAs in hypoxia-related disorders. J Biosci 2018. [DOI: 10.1007/s12038-018-9789-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Matboli M, Shafei AE, Azazy AE, Reda M, El-Khazragy N, Nagy AA, Ali MA, Sobhi M, Abdel-Rahman O. Clinical evaluation of circulating miR-548a-3p and -20a expression in malignant pleural mesothelioma patients. Biomark Med 2018; 12:129-139. [PMID: 29338319 DOI: 10.2217/bmm-2017-0224] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AIM miRNAs may act as promising diagnostic and prognostic biomarkers of mesothelioma. This study integrates serum miR-548a-3p and miR-20a expression based on in silico data analysis followed by clinical validation in malignant mesothelioma patients (malignant pleural mesothelioma [MPM]). PATIENTS & METHODS Serum miR-548a-3p and miR-20a level was assessed in the serum of patients with MPM, chronic asbestos exposure and healthy volunteers by quantitative real-time PCR. RESULTS The expression of serum miR-548a-3p and miR-20a was positive in 91.6 and 96.7% MPM patients, respectively. Both miRNAs were able to segregate between cases and controls. The sensitivity of the combined chosen serum miRNAs reached 100% in the diagnosis of MPM. CONCLUSION The current work revealed that sera miR-548a-3p and miR-20a may serve as promising novel diagnostic tools for MPM.
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Affiliation(s)
- Marwa Matboli
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Ain Shams University, Medical Ain Shams Research Center (MASRI). PO Box 11381, Abbassia, Cairo, Egypt
| | - Ayman E Shafei
- Biomedical Research Department, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Maged Reda
- Armed Forces College of Medicine, Cairo, Egypt
| | - Nashwa El-Khazragy
- Department of Clinical Pathology, Oncology Diagnostic Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Aly Nagy
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mahmoud A Ali
- Biomedical Research Department, Armed Forces College of Medicine, Cairo, Egypt
| | - Mohamed Sobhi
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Yan H, Ma F, Zhang Y, Wang C, Qiu D, Zhou K, Hua Y, Li Y. miRNAs as biomarkers for diagnosis of heart failure: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e6825. [PMID: 28562533 PMCID: PMC5459698 DOI: 10.1097/md.0000000000006825] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND With the rapid development of molecular biology, the kind of mircoRNA (miRNA) has been introduced into emerging role both in cardiac development and pathological procedure. Thus, we conduct this meta-analysis to find out the role of circulating miRNA as a biomarker in detecting heart failure. METHODS We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and World Health Organization clinical trials registry center to identify relevant studies up to August 2016. We performed meta-analysis in a fixed/random-effect model using Meta-disc 1.4. We used STATA 14.0 to estimate the publication bias and meta-regression. Besides, we took use of SPSS 17.0 to evaluate variance between several groups. Information on true positive, false positive, false negative, and true negative, as well as the quality of research was extracted. RESULTS We use results from 10 articles to analyze the pooled accuracy. The overall performance of total mixed miRNAs (TmiRs) detection was: pooled sensitivity, 0.74 (95% confidence interval [CI], 0.72 to 0.75); pooled specificity, 0.69 (95%CI, 0.67 to 0.71); and area under the summary receiver operating characteristic curves value (SROC), 0.7991. The miRNA-423-5p (miR-423-5p) detection was: pooled sensitivity, 0.81 (95%CI, 0.76 to 0.85); pooled specificity, 0.67 (95%CI, 0.61 to 0.73); and SROC, 0.8600. However, taken the same patients population, we extracted the data of BNP for detecting heart failure and performed meta-analysis with acceptable SROC as 0.9291. Among the variance analysis, the diagnostic performance of miR-423-5p claimed significant advantages of other pooled results. However, the combination of miRNAs and BNP could increase the accuracy of detecting of heart failure. Unfortunately, there was no dramatic advantage of miR-423-5p compared to BNP protocol. CONCLUSION Despite interstudy variability, the performance test of miRNA for detecting heart failure revealed that miR-423-5p demonstrated the potential to be a biomarker. However, other miRNAs were not able to provide enough evidence on promising diagnostic value for heart failure based on the current data. Moreover, the combination of miRNAs and BNP could work as a better method to detection. Unfortunately, BNP was still the most convinced biomarker for such disease.
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Affiliation(s)
- Hualin Yan
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
- West China Medical School
| | - Fan Ma
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
- West China Medical School
| | - Yi Zhang
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
| | - Chuan Wang
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
| | - Dajian Qiu
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
| | - Kaiyu Zhou
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
- Program for Changjiang Scholars and Innovative Research Team in University, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yimin Hua
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
- Program for Changjiang Scholars and Innovative Research Team in University, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yifei Li
- Department of Pediatric Cardiology, West China Second University Hospital
- Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital
- Department of Cardiology, Boston Children's Hospital, Harvard University, Boston, USA
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Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, Singha RS, Malakar AK, Chakraborty S. Interplay between miRNAs and human diseases. J Cell Physiol 2017; 233:2007-2018. [PMID: 28181241 DOI: 10.1002/jcp.25854] [Citation(s) in RCA: 280] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are endogenous, non-coding RNAs, which have evoked a great deal of interest due to their importance in many aspects of homeostasis and diseases. MicroRNAs are stable and are essential components of gene regulatory networks. They play a crucial role in healthy individuals and their dysregulations have also been implicated in a wide range of diseases, including diabetes, cardiovascular disease, kidney disease, and cancer. This review summarized the current understanding of interactions between miRNAs and different diseases and their role in disease diagnosis and therapy.
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Affiliation(s)
- Prosenjit Paul
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Debasree Sarkar
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | | | - Musfhia Rahman
- Department of Biotechnology, Assam University, Silchar, Assam, India
| | - Minakshi Bari
- Department of Biotechnology, Assam University, Silchar, Assam, India
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de Gonzalo-Calvo D, Quezada M, Campuzano O, Perez-Serra A, Broncano J, Ayala R, Ramos M, Llorente-Cortes V, Blasco-Turrión S, Morales F, Gonzalez P, Brugada R, Mangas A, Toro R. Familial dilated cardiomyopathy: A multidisciplinary entity, from basic screening to novel circulating biomarkers. Int J Cardiol 2017; 228:870-880. [PMID: 27889554 DOI: 10.1016/j.ijcard.2016.11.045] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 09/23/2016] [Accepted: 11/05/2016] [Indexed: 12/11/2022]
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Zeng Z, Wang K, Li Y, Xia N, Nie S, Lv B, Zhang M, Tu X, Li Q, Tang T, Cheng X. Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4 + T cells by targeting Myc in patients with dilated cardiomyopathy. J Biol Chem 2016; 292:6004-6013. [PMID: 27974462 DOI: 10.1074/jbc.m116.765107] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/06/2016] [Indexed: 11/06/2022] Open
Abstract
CD4+ T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4+ T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4+ T cell activation in DCM. CD4+ T cells from DCM patients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4+ T cells revealed a distinct pattern of miRNA expression in CD4+ T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4+ T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3'-UTR, thus identifying it as an miR-451a target in T cells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up-regulated at the mRNA level in CD4+ T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4+ T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM.
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Affiliation(s)
- Zhipeng Zeng
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Ke Wang
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Yuanyuan Li
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Ni Xia
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Shaofang Nie
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Bingjie Lv
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Min Zhang
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Xin Tu
- the Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, 430074 Wuhan, China
| | - Qianqian Li
- the Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, 430074 Wuhan, China
| | - Tingting Tang
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
| | - Xiang Cheng
- From the Laboratory of Cardiovascular Immunology, Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, 430022 Wuhan and
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Dahiya N, Sarachana T, Kulkarni S, Wood WH, Zhang Y, Becker KG, Wang BD, Atreya CD. miR-570 interacts with mitochondrial ATPase subunit g (ATP5L) encoding mRNA in stored platelets. Platelets 2016; 28:74-81. [PMID: 27561077 DOI: 10.1080/09537104.2016.1203405] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Loss of platelet quality during ex vivo storage is a major concern in the transfusion medicine field and it has been known that platelet mitochondrial dysfunction is associated with storage time. In the last decade, small noncoding RNAs also known as microRNAs (miRNAs) have been reported to regulate key cellular processes through their target sequence interactions with selected mRNAs. In this study, we focused on understanding the mechanisms of platelet mitochondrial dysfunction during storage through miRNA regulation of mRNAs. RNA was isolated from day 0, day 5, and day 9 of stored human leukocyte-depleted platelets and subjected to differential miRNA and mRNA profiling. The miRNA profiling identified several miRNAs at low levels including a set of 12 different miR-548 family members (miR-548a-3p, miR-548aa, miR-548x, miR-548ac, miR-548c-3p, miR-603, miR-548aj, miR-548ae, miR-548z, miR-548u, miR-548al, and miR-570-3p). The mRNA profiling identified, among many, the mitochondrial ATP synthase subunit g (ATP5L) mRNA at high levels during storage. Target Scan algorithm for potential targets of miR-570-3p also identified ATP5L as one of its targets. We further identified two target sites for miR-570-3p in the 3' untranslated region (3'UTR) of ATP5L mRNA. While ATP5L is a subunit of F0ATPase complex, its function is not established yet. Overexpression of miR-570-3p in platelets resulted in reduced levels of ATP5L mRNA and concomitant ATP loss. These experimental results provide first-time insights into the miRNA-mRNA interactions underlying mitochondrial dysfunction in ex vivo stored platelets and warrants further investigation.
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Affiliation(s)
- Neetu Dahiya
- a Section of Cell Biology, Laboratory of Cellular Hematology, Division of Hematology, Center for Biologics Evaluation and Research, US Food and Drug Administration , Silver Spring , MD , USA
| | - Tewarit Sarachana
- a Section of Cell Biology, Laboratory of Cellular Hematology, Division of Hematology, Center for Biologics Evaluation and Research, US Food and Drug Administration , Silver Spring , MD , USA.,b Department of Clinical Chemistry, Faculty of Allied Health Sciences , Chulalongkorn University , Bangkok , Thailand
| | - Sandhya Kulkarni
- a Section of Cell Biology, Laboratory of Cellular Hematology, Division of Hematology, Center for Biologics Evaluation and Research, US Food and Drug Administration , Silver Spring , MD , USA
| | - William H Wood
- c Laboratory of Genetics, National Institute on Aging , Baltimore , MD , USA
| | - Yongqing Zhang
- c Laboratory of Genetics, National Institute on Aging , Baltimore , MD , USA
| | - Kevin G Becker
- c Laboratory of Genetics, National Institute on Aging , Baltimore , MD , USA
| | - Bi-Dar Wang
- d Department of Pharmacology and Physiology , The George Washington School of Medicine and Health Sciences , Washington , DC , USA
| | - Chintamani D Atreya
- a Section of Cell Biology, Laboratory of Cellular Hematology, Division of Hematology, Center for Biologics Evaluation and Research, US Food and Drug Administration , Silver Spring , MD , USA
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Zhao G, Wang T, Huang QK, Pu M, Sun W, Zhang ZC, Ling R, Tao KS. MicroRNA-548a-5p promotes proliferation and inhibits apoptosis in hepatocellular carcinoma cells by targeting Tg737. World J Gastroenterol 2016; 22:5364-5373. [PMID: 27340352 PMCID: PMC4910657 DOI: 10.3748/wjg.v22.i23.5364] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 04/04/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether Tg737 is regulated by microRNA-548a-5p (miR-548a-5p), and correlates with hepatocellular carcinoma (HCC) cell proliferation and apoptosis.
METHODS: Assays of loss of function of Tg737 were performed by the colony formation assay, CCK assay and cell cycle assay in HCC cell lines. The interaction between miR-548a-5p and its downstream target, Tg737, was evaluated by a dual-luciferase reporter assay and quantitative real-time polymerase chain reaction. Tg737 was then up-regulated in HCC cells to evaluate its effect on miR-548a-5p regulation. HepG2 cells stably overexpressing miR-548a-5p or miR-control were also subcutaneously inoculated into nude mice to evaluate the effect of miR-548a-5p up-regulation on in vivo tumor growth. As the final step, the effect of miR-548a-5p on the apoptosis induced by cisplatin was evaluated by flow cytometry.
RESULTS: Down-regulation of Tg737, which is a target gene of miR-548a-5p, accelerated HCC cell proliferation, and miR-548a-5p promoted HCC cell proliferation in vitro and in vivo. Like the down-regulation of Tg737, overexpression of miR-548a-5p in HCC cell lines promoted cell proliferation, increased colony forming ability and hampered cell apoptosis. In addition, miR-548a-5p overexpression increased HCC cell growth in vivo. MiR-548a-5p down-regulated Tg737 expression through direct contact with its 3’ untranslated region (UTR), and miR-548a-5p expression was negatively correlated with Tg737 levels in HCC specimens. Restoring Tg737 (without the 3’UTR) significantly hampered miR-548a-5p induced cell proliferation, and rescued the miR-548a-5p induced cell proliferation inhibition and apoptosis induced by cisplatin.
CONCLUSION: MiR-548a-5p negatively regulates the tumor inhibitor gene Tg737 and promotes tumorigenesis in vitro and in vivo, indicating its potential as a novel therapeutic target for HCC.
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Schulte C, Westermann D, Blankenberg S, Zeller T. Diagnostic and prognostic value of circulating microRNAs in heart failure with preserved and reduced ejection fraction. World J Cardiol 2015; 7:843-860. [PMID: 26730290 PMCID: PMC4691811 DOI: 10.4330/wjc.v7.i12.843] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/28/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023] Open
Abstract
microRNAs (miRNAs) are powerful regulators of posttranscriptional gene expression and play an important role in pathophysiological processes. Circulating miRNAs can be quantified in body liquids and are promising biomarkers in numerous diseases. In cardiovascular disease miRNAs have been proven to be reliable diagnostic biomarkers for different disease entities. In cardiac fibrosis (CF) and heart failure (HF) dysregulated circulating miRNAs have been identified, indicating their promising applicability as diagnostic biomarkers. Some miRNAs were successfully tested in risk stratification of HF implementing their potential use as prognostic biomarkers. In this respect miRNAs might soon be implemented in diagnostic clinical routine. In the young field of miRNA based research advances have been made in identifying miRNAs as potential targets for the treatment of experimental CF and HF. Promising study results suggest their potential future application as therapeutic agents in treatment of cardiovascular disease. This article summarizes the current state of the various aspects of miRNA research in the field of CF and HF with reduced ejection fraction as well as preserved ejection fraction. The review provides an overview of the application of circulating miRNAs as biomarkers in CF and HF and current approaches to therapeutically utilize miRNAs in this field of cardiovascular disease.
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Chang CW, Wu HC, Terry MB, Santella RM. microRNA Expression in Prospectively Collected Blood as a Potential Biomarker of Breast Cancer Risk in the BCFR. Anticancer Res 2015; 35:3969-77. [PMID: 26124344 PMCID: PMC4776637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
BACKGROUND/AIM Current breast cancer risk assessment models have moderate discriminatory ability. We evaluated whether microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMC) could be a useful biomarker of risk in high-risk women. MATERIALS AND METHODS Next-generation sequencing evaluated miR expression in PBMCs of 20 women who were unaffected at the time of recruitment and later diagnosed with breast cancer and 20 unaffected women. RESULTS Out of the 5 miRNAs identified as potential risk markers, miR-144-3p, miR-451a, miR-144-5p and miR-183-5p were up-regulated, while miR-708-5p was down-regulated. We then evaluated these miRs in 28 additional case/control pairs using quantitative reverse transcription polymerase chain reaction (PCR). None of the results in the validation sample were statistically significant possibly due to the much longer interval between blood collection and diagnosis in the validation set. CONCLUSIONS Differentially expressed miRNAs from PBMCs may be potential non-invasive biomarkers for breast cancer prediction. Larger prospective studies are required to confirm whether our findings with specific miRNA loci were related to timing before diagnosis.
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Affiliation(s)
- Chin-Wen Chang
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, U.S.A
| | - Hui-Chen Wu
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, U.S.A
| | - Mary Beth Terry
- Department of Epidemiology, Mailman School of Public Health of Columbia University, New York, NY, U.S.A. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, U.S.A
| | - Regina M Santella
- Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY, U.S.A. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, U.S.A.
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Weber K, Rostert N, Bauersachs S, Wess G. Serum microRNA profiles in cats with hypertrophic cardiomyopathy. Mol Cell Biochem 2015; 402:171-80. [PMID: 25573325 DOI: 10.1007/s11010-014-2324-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 12/23/2014] [Indexed: 12/22/2022]
Abstract
The role of microRNAs (miRNAs) in the pathogenesis of heart diseases of humans and rodents, as well as their diagnostic potential, has recently received much attention, but comparable studies for spontaneous disease models in the domestic cat are missing. Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats. The pathology is largely unknown, but is suspected to be influenced by genetic background. In this study, we examined the miRNA profiles in the serum of cats with stable congestive heart failure caused by HCM (n = 11) and healthy control cats (n = 12) using miRNA arrays. 965 out of 2026 miRNAs could be detected in at least six samples of either of the groups. Eleven mammalian miRNAs were differentially expressed between the groups with a fold change ≥ 1.6. Hierarchical cluster analysis resulted in distinct separation of the two groups. After correction for multiple testing (adjusted p < 0.05), a higher expression of miR-381-3p, miR-486-3p, miR-4751, miR-476c-3p, miR-5700, miR-513a-3p, and miR-320e in the HCM group was confirmed. Additionally, miR-1246 was found to be upregulated 3-fold in the HCM group using quantitative RT-PCR. Software analysis of the significantly regulated miRNAs revealed 49 mRNA targets involved in cardiac hypertrophy. Cats with primary HCM show a distinct miRNA profile that includes miRNAs that have already been shown to be differentially regulated in human patients and rodent models for cardiac disease. Studying HCM as a spontaneous cardiac disease of the cat may help to reveal additional pathophysiologic pathways.
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Affiliation(s)
- K Weber
- Faculty of Veterinary Medicine, Clinic of Small Animal Medicine, Centre for Clinical Veterinary Medicine, LMU Munich, Veterinaerstr. 13, 80539, Munich, Germany,
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Moura J, Børsheim E, Carvalho E. The Role of MicroRNAs in Diabetic Complications-Special Emphasis on Wound Healing. Genes (Basel) 2014; 5:926-56. [PMID: 25268390 PMCID: PMC4276920 DOI: 10.3390/genes5040926] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/05/2014] [Accepted: 09/10/2014] [Indexed: 12/19/2022] Open
Abstract
Overweight and obesity are major problems in today’s society, driving the prevalence of diabetes and its related complications. It is important to understand the molecular mechanisms underlying the chronic complications in diabetes in order to develop better therapeutic approaches for these conditions. Some of the most important complications include macrovascular abnormalities, e.g., heart disease and atherosclerosis, and microvascular abnormalities, e.g., retinopathy, nephropathy and neuropathy, in particular diabetic foot ulceration. The highly conserved endogenous small non-coding RNA molecules, the micro RNAs (miRNAs) have in recent years been found to be involved in a number of biological processes, including the pathogenesis of disease. Their main function is to regulate post-transcriptional gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation, suppression of translation or even gene activation. These molecules are promising therapeutic targets and demonstrate great potential as diagnostic biomarkers for disease. This review aims to describe the most recent findings regarding the important roles of miRNAs in diabetes and its complications, with special attention given to the different phases of diabetic wound healing.
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Affiliation(s)
- João Moura
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal.
| | - Elisabet Børsheim
- Arkansas Children's Nutrition Center, Little Rock, Arkansas, AR 72202, USA.
| | - Eugenia Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal.
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Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. ACTA ACUST UNITED AC 2014; 8:368-75. [PMID: 24794206 DOI: 10.1016/j.jash.2014.03.324] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 03/21/2014] [Accepted: 03/21/2014] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRs), as essential gene expression regulators, modulate cardiovascular development and disease and thus they are emerging as potential biomarkers and therapeutic targets in cardiovascular disease, including hypertension. We assessed the expression levels of the microRNAs miR-9 and miR-126 in 60 patients with untreated essential hypertension and 29 healthy individuals. All patients underwent two-dimensional echocardiography and 24-hour ambulatory blood pressure monitoring. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-9 (9.69 ± 1.56 vs 41.08 ± 6.06; P < .001) and miR-126 (3.88 ± 0.47 vs 8.96 ± 1.69; P < .001) expression levels compared with healthy controls. In hypertensive patients, miR-9 expression levels showed a significant positive correlation (r = 0.437; P < .001) with left ventricular mass index. Furthermore, both miR-9 (r = 0.312; P = .015) and miR-126 (r = 0.441; P < .001) expression levels in hypertensive patients showed significant positive correlations with the 24-hour mean pulse pressure. Our data reveal that miR-9 and miR-126 are closely related to essential hypertension in humans, as they show a distinct expression profile in hypertensive patients relative to healthy individuals, and they are associated with clinical prognostic indices of hypertensive target-organ damage in hypertensive patients. Thus, they may possibly represent potential biomarkers and candidate therapeutic targets in essential hypertension.
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Affiliation(s)
- Joanna E Kontaraki
- Molecular Cardiology Laboratory, School of Medicine, University of Crete, Greece.
| | - Maria E Marketou
- Department of Cardiology, Heraklion University Hospital, Crete, Greece
| | | | | | - Panos E Vardas
- Department of Cardiology, Heraklion University Hospital, Crete, Greece
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Condorelli G, Latronico MVG, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol 2014; 63:2177-87. [PMID: 24583309 DOI: 10.1016/j.jacc.2014.01.050] [Citation(s) in RCA: 285] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/17/2014] [Accepted: 01/28/2014] [Indexed: 12/15/2022]
Abstract
Over the last few years, the field of microribonucleic acid (miRNA) in cardiovascular biology and disease has expanded at an incredible pace. miRNAs are themselves part of a larger family, that of non-coding RNAs, the importance of which for biological processes is starting to emerge. miRNAs are ~22-nucleotide-long RNA sequences that can legate messenger (m)RNAs at partially complementary binding sites, and hence regulate the rate of protein synthesis by altering the stability of the targeted mRNAs. In the cardiovascular system, miRNAs have been shown to be critical regulators of development and physiology. They control basic functions in virtually all cell types relevant to the cardiovascular system (such as endothelial cells, cardiac muscle, smooth muscle, inflammatory cells, and fibroblasts) and, thus, are directly involved in the pathophysiology of many cardiovascular diseases. As a result of their role in disease, they are being studied for exploitation in diagnostics, prognostics, and therapeutics. However, there are still significant obstacles that need to be overcome before they enter the clinical arena. We present here a review of the literature and outline the directions toward their use in the clinic.
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Affiliation(s)
- Gianluigi Condorelli
- Cardiovascular Research Center, Humanitas Research Hospital, Rozzano, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano, Italy; Institute of Genetics and Biomedical Research, National Research Council of Italy, Rome, Italy.
| | | | - Elena Cavarretta
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "La Sapienza", Latina, Italy
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Nadorp B, Soreq H. Predicted overlapping microRNA regulators of acetylcholine packaging and degradation in neuroinflammation-related disorders. Front Mol Neurosci 2014; 7:9. [PMID: 24574962 PMCID: PMC3918661 DOI: 10.3389/fnmol.2014.00009] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 01/21/2014] [Indexed: 01/13/2023] Open
Abstract
MicroRNAs (miRNAs) can notably control many targets each and regulate entire cellular pathways, but whether miRNAs can regulate complete neurotransmission processes is largely unknown. Here, we report that miRNAs with complementary sequence motifs to the key genes involved in acetylcholine (ACh) synthesis and/or packaging show massive overlap with those regulating ACh degradation. To address this topic, we first searched for miRNAs that could target the 3′-untranslated regions of the choline acetyltransferase (ChAT) gene that controls ACh synthesis; the vesicular ACh transporter (VAChT), encoded from an intron in the ChAT gene and the ACh hydrolyzing genes acetyl- and/or butyrylcholinesterase (AChE, BChE). Intriguingly, we found that many of the miRNAs targeting these genes are primate-specific, and that changes in their levels associate with inflammation, anxiety, brain damage, cardiac, neurodegenerative, or pain-related syndromes. To validate the in vivo relevance of this dual interaction, we selected the evolutionarily conserved miR-186, which targets both the stress-inducible soluble “readthrough” variant AChE-R and the major peripheral cholinesterase BChE. We exposed mice to predator scent stress and searched for potential associations between consequent changes in their miR-186, AChE-R, and BChE levels. Both intestinal miR-186 as well as BChE and AChE-R activities were conspicuously elevated 1 week post-exposure, highlighting the previously unknown involvement of miR-186 and BChE in psychological stress responses. Overlapping miRNA regulation emerges from our findings as a recently evolved surveillance mechanism over cholinergic neurotransmission in health and disease; and the corresponding miRNA details and disease relevance may serve as a useful resource for studying the molecular mechanisms underlying this surveillance.
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Affiliation(s)
- Bettina Nadorp
- Department of Biological Chemistry and the Center for Bioengineering, The Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem Jerusalem, Israel
| | - Hermona Soreq
- Department of Biological Chemistry and the Center for Bioengineering, The Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem Jerusalem, Israel
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