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Papadopoulos KI, Papadopoulou A, Aw TC. MicroRNA-155 modulation by renin-angiotensin system inhibitors may underlie their enigmatic role in COVID-19. World J Exp Med 2025; 15:100748. [DOI: 10.5493/wjem.v15.i2.100748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 01/18/2025] [Accepted: 02/06/2025] [Indexed: 04/16/2025] Open
Abstract
Severe acute respiratory coronavirus-2 (SARS-CoV-2) infection course differs between the young and healthy and the elderly with co-morbidities. In the latter a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm has been described with an unrestrained renin-angiotensin (Ang) system (RAS). RAS inhibitors [Ang converting enzyme inhibitors and Ang II type 1 receptor (AT1R) blockers] while appearing appropriate in COVID-19, display enigmatic effects ranging from protection to harm. MicroRNA-155 (miR-155)-induced translational repression of key cardiovascular (CV) genes (i.e., AT1R) restrains SARS-CoV-2-engendered RAS hyperactivity to tolerable and SARS-CoV-2-protective CV phenotypes supporting a protective erythropoietin (EPO) evolutionary landscape. MiR-155’s disrupted repression of the AT1R 1166C-allele associates with adverse CV and COVID-19 outcomes, confirming its decisive role in RAS modulation. RAS inhibition disrupts this miR-155-EPO network by further lowering EPO and miR-155 in COVID-19 with co-morbidities, thereby allowing unimpeded RAS hyperactivity to progress precariously. Current pharmacological interventions in COVID-19 employing RAS inhibition should consider these complex but potentially detrimental miR-155/EPO-related effects.
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Affiliation(s)
| | - Alexandra Papadopoulou
- Department of Occupational and Environmental Health Services, Feelgood Lund, Lund 223-63, Skåne, Sweden
| | - Tar Choon Aw
- Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
- Department of Medicine, National University of Singapore, Singapore 119228, Singapore
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Khan K, Khan A, Rahman ZU, Khan F, Latief N, Fazal N. Genetic Polymorphism in miRNA Genes and Their Association with susceptibility of Coronary Heart Disease: An Updated Review. Pathol Res Pract 2024; 264:155675. [PMID: 39488988 DOI: 10.1016/j.prp.2024.155675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/18/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Coronary heart disease (CHD) remains a major public health concern worldwide, with a complex interplay of genetic, environmental and lifestyle factors contributing to its pathogenesis. The potential significance of microRNAs (miRNAs) in the onset and progression of CHD has attracted increasing attention in recent years. Small non-coding RNA molecules called miRNAs control gene expression at the post-transcriptional level. Dysregulation of miRNAs has been linked to a variety of biological processes, including cell division, proliferation, apoptosis, and inflammation. Numerous research studies have looked into the relationship between genetic variants in miRNA genes and CHD susceptibility. This review highlights the recent research work carried out to identify the relationship of miRNA genes polymorphism with the progression and susceptibility of CHD. Such studies could pave the way for the development of personalized strategies for CHD prevention and treatment based on an individual's genetic profile.
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Affiliation(s)
- Khalid Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Aakif Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Zia Ur Rahman
- University Institute of Medical Laboratory Technology, the University of Lahore, Pakistan
| | - Faisal Khan
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Noreen Latief
- National Centre of Excellence in Molecular Biology, University of the Punjab, Pakistan
| | - Numan Fazal
- University Institute of Medical Laboratory Technology, the University of Lahore, Pakistan.
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3
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Andiappan R, Govindan R, Ramasamy T, Poomarimuthu M. Circulating miR-133a-3p and miR-451a as potential biomarkers for diagnosis of coronary artery disease. Acta Cardiol 2024; 79:813-823. [PMID: 39373072 DOI: 10.1080/00015385.2024.2410599] [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: 07/06/2023] [Revised: 09/03/2024] [Accepted: 09/26/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Coronary artery disease (CAD) remains the leading cause of mortality and morbidity around the world. Despite significant progress in the diagnosis and treatment of cardiovascular diseases, still there is a clinical need to identify novel biomarkers for early diagnosis and treatment of CAD. The aim of the study is to investigate circulating miRNAs in CAD patients to identify potential biomarkers for early detection and therapeutic management of CAD. METHODS We assessed the expression of different candidate miRNAs (miR-21-5p, miR-133a-3p, miR-221-3p, miR-451a and miR-584-5p) in plasma from 50 CAD patients and 50 controls by qRT-PCR analysis. RESULTS The expression levels of miR-133a-3p (fold change (FC): 28.05, p < 0.0001), miR-451a (FC: 27.47, p < 0.0001), miR-584-5p (FC: 7.89, p < 0.0001), miR-21-5p (FC: 5.35, p < 0.0001) and miR-221-3p (FC: 5.03, p < 0.0001) were significantly up-regulated in CAD patients compared to controls. Receiver operating characteristic curve analysis showed that miR-133a-3p and miR-451a were powerful biomarkers for detecting CAD. CONCLUSIONS Our results suggested that miR-21-5p, miR-133a-3p, miR-221-3p, miR-451a and miR-584-5p may serve as independent biomarkers for CAD. Further, the combination of miR-133a-3p and miR-451a could be used as a specific signature in CAD diagnosis.
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Affiliation(s)
- Rathinavel Andiappan
- Department of Cardio Vascular Thoracic Surgery, Madurai Medical College & Government Rajaji Hospital, Madurai, Tamil Nadu, India
| | - Ramajayam Govindan
- Multidisciplinary Research Unit, Madurai Medical College, Madurai, Tamil Nadu, India
| | - Thirunavukkarasu Ramasamy
- Maternal-Child health Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India
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Boen HM, Cherubin M, Franssen C, Gevaert AB, Witvrouwen I, Bosman M, Guns PJ, Heidbuchel H, Loeys B, Alaerts M, Van Craenenbroeck EM. Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2024; 6:183-199. [PMID: 38774014 PMCID: PMC11103047 DOI: 10.1016/j.jaccao.2023.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 05/24/2024] Open
Abstract
Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.
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Affiliation(s)
- Hanne M. Boen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Martina Cherubin
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Constantijn Franssen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Andreas B. Gevaert
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Isabel Witvrouwen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Matthias Bosman
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Hein Heidbuchel
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Bart Loeys
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Maaike Alaerts
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Emeline M. Van Craenenbroeck
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
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5
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Searles CD. MicroRNAs and Cardiovascular Disease Risk. Curr Cardiol Rep 2024; 26:51-60. [PMID: 38206553 PMCID: PMC10844442 DOI: 10.1007/s11886-023-02014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2023] [Indexed: 01/12/2024]
Abstract
PURPOSE OF REVIEW MicroRNAs (miRNAs)-short, non-coding RNAs-play important roles in almost all aspects of cardiovascular biology, and changes in intracellular miRNA expression are indicative of cardiovascular disease development and progression. Extracellular miRNAs, which are easily measured in blood and can be reflective of changes in intracellular miRNA levels, have emerged as potential non-invasive biomarkers for disease. This review summarizes current knowledge regarding miRNAs as biomarkers for assessing cardiovascular disease risk and prognosis. RECENT FINDINGS Numerous studies over the last 10-15 years have identified associations between extracellular miRNA profiles and cardiovascular disease, supporting the potential use of extracellular miRNAs as biomarkers for risk stratification. However, clinical application of extracellular miRNA profiles has been hampered by poor reproducibility and inter-study variability that is due largely to methodological differences between studies. While recent studies indicate that circulating extracellular miRNAs are promising biomarkers for cardiovascular disease, evidence for clinical implementation is lacking. This highlights the need for larger, well-designed studies that use standardized methods for sample preparation, miRNA isolation, quantification, and normalization.
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Affiliation(s)
- Charles D Searles
- Emory University School of Medicine and Atlanta VA Health Care System, 1670 Clairmont Road, Decatur, GA, 30033, USA.
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Macvanin MT, Gluvic ZM, Klisic AN, Manojlovic MS, Suri JS, Rizzo M, Isenovic ER. The Link between miRNAs and PCKS9 in Atherosclerosis. Curr Med Chem 2024; 31:6926-6956. [PMID: 37990898 DOI: 10.2174/0109298673262124231102042914] [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: 05/12/2023] [Revised: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 11/23/2023]
Abstract
Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, and miRNA levels manipulation by therapeutic agents.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran M Gluvic
- Department of Endocrinology and Diabetes, School of Medicine, University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra N Klisic
- Faculty of Medicine, Center for Laboratory Diagnostic, Primary Health Care Center, University of Montenegro, Podgorica, Montenegro
| | - Mia S Manojlovic
- Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Novi Sad, Serbia
| | - Jasjit S Suri
- Stroke Monitoring and Diagnostic Division, Athero- Point™, Roseville, CA95661, USA
| | - Manfredi Rizzo
- Department of Health Promotion, School of Medicine, Mother and Child Care and Medical Specialties (Promise), University of Palermo, Palermo, Italy
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Papadopoulos KI, Papadopoulou A, Aw TC. MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation: implications for innovative type 2 diabetes mellitus management. World J Diabetes 2023; 14:1334-1340. [PMID: 37771329 PMCID: PMC10523232 DOI: 10.4239/wjd.v14.i9.1334] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/18/2023] [Accepted: 07/13/2023] [Indexed: 09/13/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a lifelong condition and a threat to human health. Thorough understanding of its pathogenesis is acutely needed in order to devise innovative, preventative, and potentially curative pharmacological interventions. MicroRNAs (miRNA), are small, non-coding, one-stranded RNA molecules, that can target and silence around 60% of all human genes through translational repression. MiR-155 is an ancient, evolutionarily well-conserved miRNA, with distinct expression profiles and multifunctionality, and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular conditions, and particularly diabetes mellitus. MiR-155 Levels are progressively reduced in aging, obesity, sarcopenia, and T2DM. Thus, the loss of coordinated repression of multiple miR-155 targets acting as negative regulators, such as C/EBPβ, HDAC4, and SOCS1 impacts insulin signaling, deteriorating glucose homeostasis, and causing insulin resistance (IR). Moreover, deranged regulation of the renin angiotensin aldo-sterone system (RAAS) through loss of Angiotensin II Type 1 receptor downregulation, and negated repression of ETS-1, results in unopposed detrimental Angiotensin II effects, further promoting IR. Finally, loss of BACH1 and SOCS1 repression abolishes cytoprotective, anti-oxidant, anti-apoptotic, and anti-inflammatory cellular pathways, and promotes β-cell loss. In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels, strategies to increase an ailing miR-155 production in T2DM, e.g., the use of metformin, mineralocorticoid receptor blockers (spironolactone, eplerenone, finerenone), and verapamil, alone or in various combinations, represent current treatment options. In the future, direct tissue delivery of miRNA analogs is likely.
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Affiliation(s)
| | - Alexandra Papadopoulou
- Occupational and Environmental Health Services, Feelgood Lund, Lund 223-63, Skåne, Sweden
| | - Tar-Choon Aw
- Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore, Singapore
- Department of Medicine, National University of Singapore, Singapore 119228, Singapore, Singapore
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Novák J, Maceková S, Héžová R, Máchal J, Zlámal F, Hlinomaz O, Rezek M, Souček M, Vašků A, Slabý O, Bienertová-Vašků J. Polymorphism rs7079 in miR-31/-584 Binding Site in Angiotensinogen Gene Associates with Earlier Onset of Coronary Artery Disease in Central European Population. Genes (Basel) 2022; 13:1981. [PMID: 36360218 PMCID: PMC9690213 DOI: 10.3390/genes13111981] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Angiotensinogen (AGT) represents a key component of the renin-angiotensin-aldosterone system (RAAS). Polymorphisms in the 3' untranslated region (3'UTR) of the AGT gene may alter miRNA binding and cause disbalance in the RAAS. Within this study, we evaluated the possible association of AGT +11525C/A (rs7079) with the clinical characteristics of patients with coronary artery diseases (CAD). Selective coronarography was performed in 652 consecutive CAD patients. Clinical characteristics of the patients, together with peripheral blood samples for DNA isolation, were collected. The genotyping of rs7079 polymorphism was performed with TaqMan® SNP Genotyping Assays. We observed that patients with the CC genotype were referred for coronarography at a younger age compared to those with the AA+CA genotypes (CC vs. AA+CA: 59.1 ± 9.64 vs. 60.91 ± 9.5 (years), p = 0.045). Moreover, according to the logistic regression model, patients with the CC genotype presented more often with restenosis than those with the CA genotype (p = 0.0081). In conclusion, CC homozygotes for rs7079 present with CAD symptoms at a younger age compared with those with the AA+CA genotype, and they are more prone to present with restenosis compared with heterozygotes.
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Affiliation(s)
- Jan Novák
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
- Second Department of Internal Medicine, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
- Ondrej Slaby Joint Research Group, Central European Institute of Technology and Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Soňa Maceková
- Second Department of Internal Medicine, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
| | - Renata Héžová
- Ondrej Slaby Joint Research Group, Central European Institute of Technology and Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Jan Máchal
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
- Department of Cardiovascular Diseases, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
- International Clinical Research Center, St Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Filip Zlámal
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Ota Hlinomaz
- Department of Cardiovascular Diseases, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
- International Clinical Research Center, St Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Michal Rezek
- Department of Cardiovascular Diseases, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
- International Clinical Research Center, St Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Miroslav Souček
- Second Department of Internal Medicine, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 656 91 Brno, Czech Republic
- International Clinical Research Center, St Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Anna Vašků
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Ondřej Slabý
- Ondrej Slaby Joint Research Group, Central European Institute of Technology and Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Julie Bienertová-Vašků
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
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Brown C, Mantzaris M, Nicolaou E, Karanasiou G, Papageorgiou E, Curigliano G, Cardinale D, Filippatos G, Memos N, Naka KK, Papakostantinou A, Vogazianos P, Ioulianou E, Shammas C, Constantinidou A, Tozzi F, Fotiadis DI, Antoniades A. A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research. CARDIO-ONCOLOGY 2022; 8:16. [PMID: 36071532 PMCID: PMC9450324 DOI: 10.1186/s40959-022-00142-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/02/2022] [Indexed: 12/01/2022]
Abstract
Breast cancer patients are at a particularly high risk of cardiotoxicity from chemotherapy having a detrimental effect on quality-of-life parameters and increasing the risk of mortality. Prognostic biomarkers would allow the management of therapies to mitigate the risks of cardiotoxicity in vulnerable patients and a key potential candidate for such biomarkers are microRNAs (miRNA). miRNAs are post-transcriptional regulators of gene expression which can also be released into the circulatory system and have been associated with the progression of many chronic diseases including many types of cancer. In this review, the evidence for the potential application of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity (CIC) in breast cancer patientsis evaluated and a simple meta-analysis is performed to confirm the replication status of each reported miRNA. Further selection of miRNAs is performed by reviewing the reported associations of each miRNA with other cardiovascular conditions. Based on this research, the most representative panels targeting specific chemotherapy agents and treatment regimens are suggested, that contain several informative miRNAs, including both general markers of cardiac damage as well as those for the specific cancer treatments.
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10
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Decoding microRNA drivers in Atherosclerosis. Biosci Rep 2022; 42:231479. [PMID: 35758143 PMCID: PMC9289798 DOI: 10.1042/bsr20212355] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/17/2022] [Accepted: 06/26/2022] [Indexed: 11/17/2022] Open
Abstract
An estimated 97% of the human genome consists of non-protein-coding sequences. As our understanding of genome regulation improves, this has led to the characterization of a diverse array of non-coding RNAs (ncRNA). Among these, micro-RNAs (miRNAs) belong to the short ncRNA class (22–25 nucleotides in length), with approximately 2500 miRNA genes encoded within the human genome. From a therapeutic perspective, there is interest in exploiting miRNA as biomarkers of disease progression and response to treatments, as well as miRNA mimics/repressors as novel medicines. miRNA have emerged as an important class of RNA master regulators with important roles identified in the pathogenesis of atherosclerotic cardiovascular disease. Atherosclerosis is characterized by a chronic inflammatory build-up, driven largely by low-density lipoprotein cholesterol accumulation within the artery wall and vascular injury, including endothelial dysfunction, leukocyte recruitment and vascular remodelling. Conventional therapy focuses on lifestyle interventions, blood pressure-lowering medications, high-intensity statin therapy and antiplatelet agents. However, a significant proportion of patients remain at increased risk of cardiovascular disease. This continued cardiovascular risk is referred to as residual risk. Hence, a new drug class targeting atherosclerosis could synergise with existing therapies to optimise outcomes. Here, we review our current understanding of the role of ncRNA, with a focus on miRNA, in the development and progression of atherosclerosis, highlighting novel biological mechanisms and therapeutic avenues.
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Abdallah HY, Hassan R, Fareed A, Abdelgawad M, Mostafa SA, Mohammed EAM. Identification of a circulating microRNAs biomarker panel for non-invasive diagnosis of coronary artery disease: case-control study. BMC Cardiovasc Disord 2022; 22:286. [PMID: 35751015 PMCID: PMC9233383 DOI: 10.1186/s12872-022-02711-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/09/2022] [Indexed: 12/07/2022] Open
Abstract
Background Circulating microRNAs (miRNAs) are considered a hot spot of research that can be employed for monitoring and/or diagnostic purposes in coronary artery disease (CAD). Since different disease features might be reflected on altered profiles or plasma miRNAs concentrations, a combination of miRNAs can provide more reliable non-invasive biomarkers for CAD. Subjects and methods We investigated a panel of 14-miRNAs selected using bioinformatics databases and current literature searching for miRNAs involved in CAD using quantitative real-time PCR technique in 73 CAD patients compared to 73 controls followed by function and pathway enrichment analysis for the 14-miRNAs. Results Our results revealed three out of the 14 circulating miRNAs understudy; miRNAs miR133a, miR155 and miR208a were downregulated. While 11 miRNAs were up-regulated in a descending order from highest fold change to lowest: miR-182, miR-145, miR-21, miR-126, miR-200b, miR-146A, miR-205, miR-135b, miR-196b, miR-140b and, miR-223. The ROC curve analysis indicated that miR-145, miR-182, miR-133a and, miR-205 were excellent biomarkers with the highest AUCs as biomarkers in CAD. All miRNAs under study except miR-208 revealed a statistically significant relation with dyslipidemia. MiR-126 and miR-155 showed significance with BMI grade, while only miR-133a showed significance with the obese patients in general. MiR-135b and miR-140b showed a significant correlation with the Wall Motion Severity Index. Pathway enrichment analysis for the miRNAS understudy revealed pathways relevant to the fatty acid biosynthesis, ECM-receptor interaction, proteoglycans in cancer, and adherens junction. Conclusion The results of this study identified a differentially expressed circulating miRNAs signature that can discriminate CAD patients from normal subjects. These results provide new insights into the significant role of miRNAs expression associated with CAD pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02711-9.
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Affiliation(s)
- Hoda Y Abdallah
- Medical Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt. .,Center of Excellence in Molecular & Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Ranya Hassan
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Ahmed Fareed
- Department of Cardiology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Mai Abdelgawad
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Sally Abdallah Mostafa
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman Abdel-Moemen Mohammed
- Medical Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.,Center of Excellence in Molecular & Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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The association of plasma levels of miR-146a, miR-27a, miR-34a, and miR-149 with coronary artery disease. Mol Biol Rep 2022; 49:3559-3567. [PMID: 35553331 DOI: 10.1007/s11033-022-07196-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/27/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Coronary artery disease (CAD) is considered to be one of the most pivotal causes of death in the world. Over the past two decades, significant changes occurred in the diagnosis, prognosis, and treatment of CAD, which has helped reduce mortality rates. microRNAs (miRs) are a class of more than 5000 non-encoding RNA molecules (21-25 nucleotides across the length) that regulate complex biological processes. Today, miRNAs are used to study cardiovascular diseases. In the present study, the expression of miR-146a،miR-27, miR-149, and miR-34a in plasma suffering from CAD and the control group were investigated. METHODS AND RESULTS The present research was performed on 30 men with CAD and 30 healthy men as controls. The expression levels of miR-146a, miR-27a, miR-149, and miR-34a in the plasma of patients with CAD and the control group were measured using real-time PCR. Also, the correlation between the expression of circulating miRs levels and biochemical LDL-C, HDL-C, BMI, and total cholesterol was evaluated. The expression of miR-27a in the plasma of the CAD group was higher than in the control group (p = 0.020). The expression of miR-146a was downregulated in CAD patients compared to normal subjects (p = 0. 026). However, the expression of miR-34a, miR-149 in the plasma of CAD patients was not significantly different with the control group. In addition to, a direct correlation was found between the expression of miR-146a and HDL-c, the expression of miR-27a and LDL-C and the expression of miR-34a and total cholesterol. Also, the negative correlation between expressions of miR-149 with BMI was reported. CONCLUSION The obtained results demonstrated that miRs were closely related to biochemical factors and it points out the fact that miRNAs can be applied as a potential strategy for diagnosis and treatment of CAD.
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13
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Mahjoob G, Ahmadi Y, Fatima rajani H, khanbabaei N, Abolhasani S. Circulating microRNAs as predictive biomarkers of coronary artery diseases in type 2 diabetes patients. J Clin Lab Anal 2022; 36:e24380. [PMID: 35349731 PMCID: PMC9102494 DOI: 10.1002/jcla.24380] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is an increasing metabolic disorder mostly resulting from unhealthy lifestyles. T2DM patients are prone to develop heart conditions such as coronary artery disease (CAD) which is a major cause of death in the world. Most clinical symptoms emerge at the advanced stages of CAD; therefore, establishing new biomarkers detectable in the early stages of the disease is crucial to enhance the efficiency of treatment. Recently, a significant body of evidence has shown alteration in miRNA levels associate with dysregulated gene expression occurring in T2DM and CAD, highlighting significance of circulating miRNAs in early detection of CAD arising from T2DM. Therefore, it seems crucial to establish a link between the miRNAs prognosing value and development of CAD in T2DM. AIM This study provides an overview on the alterations of the circulatory miRNAs in T2DM and various CADs and consider the potentials of miRNAs as biomarkers prognosing CADs in T2DM patients. MATERIALS AND METHODS Literature search was conducted for miRNAs involved in development of T2DM and CAD using the following key words: "miRNAs", "Biomarker", "Diabetes Mellitus Type 2 (T2DM)", "coronary artery diseases (CAD)". Articles written in the English language. RESULT There has been shown a rise in miR-375, miR-9, miR-30a-5p, miR-150, miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a, miR-27a, and miR-320a in T2DM; whereas, miR-126, miR-21, miR-103, miR-28-3p, miR-15a, miR-145, miR-375, miR-223 have been shown to decrease. In addition to T2DM, some miRNAs such as mirR-1, miR-122, miR-132, and miR-133 play a part in development of subclinical aortic atherosclerosis associated with metabolic syndrome. Some miRNAs increase in both T2DM and CAD such as miR-1, miR-132, miR-133, and miR-373-3-p. More interestingly, some of these miRNAs such as miR-92a elevate years before emerging CAD in T2DM. CONCLUSION dysregulation of miRNAs plays outstanding roles in development of T2DM and CAD. Also, elevation of some miRNAs such as miR-92a in T2DM patients can efficiently prognose development of CAD in these patients, so these miRNAs can be used as biomarkers in this regard.
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Affiliation(s)
- Golnoosh Mahjoob
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
| | - Yasin Ahmadi
- Department of Medical Laboratory SciencesCollege of ScienceKomar University of Science and TechnologySulaimaniIraq
| | - Huda Fatima rajani
- Department of medical biotechnologySchool of advanced sciences in medicineTehran University of medical sciencesTehranIran
| | - Nafiseh khanbabaei
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
| | - Sakhavat Abolhasani
- Department of Clinical BiochemistrySarab Faculty of Medical Sciences.SarabIran
- Department of Clinical BiochemistryTarbiat Modares UniversityTehranIran
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14
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Adam CA, Șalaru DL, Prisacariu C, Marcu DTM, Sascău RA, Stătescu C. Novel Biomarkers of Atherosclerotic Vascular Disease-Latest Insights in the Research Field. Int J Mol Sci 2022; 23:4998. [PMID: 35563387 PMCID: PMC9103799 DOI: 10.3390/ijms23094998] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
The atherosclerotic vascular disease is a cardiovascular continuum in which the main role is attributed to atherosclerosis, from its appearance to its associated complications. The increasing prevalence of cardiovascular risk factors, population ageing, and burden on both the economy and the healthcare system have led to the development of new diagnostic and therapeutic strategies in the field. The better understanding or discovery of new pathophysiological mechanisms and molecules modulating various signaling pathways involved in atherosclerosis have led to the development of potential new biomarkers, with key role in early, subclinical diagnosis. The evolution of technological processes in medicine has shifted the attention of researchers from the profiling of classical risk factors to the identification of new biomarkers such as midregional pro-adrenomedullin, midkine, stromelysin-2, pentraxin 3, inflammasomes, or endothelial cell-derived extracellular vesicles. These molecules are seen as future therapeutic targets associated with decreased morbidity and mortality through early diagnosis of atherosclerotic lesions and future research directions.
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Affiliation(s)
- Cristina Andreea Adam
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
| | - Delia Lidia Șalaru
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Cristina Prisacariu
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Dragoș Traian Marius Marcu
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Radu Andy Sascău
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
| | - Cristian Stătescu
- Institute of Cardiovascular Diseases “Prof. Dr. George I.M. Georgescu”, 700503 Iași, Romania; (C.A.A.); (C.P.); (R.A.S.); (C.S.)
- Department of Internal Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, 700115 Iași, Romania;
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15
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Noncoding RNA as Diagnostic and Prognostic Biomarkers in Cerebrovascular Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8149701. [PMID: 35498129 PMCID: PMC9042605 DOI: 10.1155/2022/8149701] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/22/2022] [Indexed: 02/06/2023]
Abstract
Noncoding RNAs (ncRNAs), such as microRNAs, long noncoding RNAs, and circular RNAs, play an important role in the pathophysiology of cerebrovascular diseases (CVDs). They are effectively detectable in body fluids, potentially suggesting new biomarkers for the early detection and prognosis of CVDs. In this review, the physiological functions of circulating ncRNAs and their potential role as diagnostic and prognostic markers in patients with cerebrovascular diseases are discussed, especially in acute ischemic stroke, subarachnoid hemorrhage, and moyamoya disease.
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16
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Chatzopoulou F, Kyritsis KA, Papagiannopoulos CI, Galatou E, Mittas N, Theodoroula NF, Papazoglou AS, Karagiannidis E, Chatzidimitriou M, Papa A, Sianos G, Angelis L, Chatzidimitriou D, Vizirianakis IS. Dissecting miRNA–Gene Networks to Map Clinical Utility Roads of Pharmacogenomics-Guided Therapeutic Decisions in Cardiovascular Precision Medicine. Cells 2022; 11:cells11040607. [PMID: 35203258 PMCID: PMC8870388 DOI: 10.3390/cells11040607] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/29/2022] [Accepted: 01/31/2022] [Indexed: 02/04/2023] Open
Abstract
MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the molecular level, it is essential to establish genomic signatures to delineate multifactorial correlations, and to unveil the variability seen in therapeutic intervention outcomes. The clinically validated miRNA biomarkers, along with the relevant SNPs identified, have to be suitably implemented in the clinical setting in order to enhance patient stratification capacity, to contribute to a better understanding of the underlying pathophysiological mechanisms, to guide the selection of innovative therapeutic schemes, and to identify innovative drugs and delivery systems. In this article, the miRNA–gene networks and the genomic signatures resulting from the SNPs will be analyzed as a method of highlighting specific gene-signaling circuits as sources of molecular knowledge which is relevant to CVDs. In concordance with this concept, and as a case study, the design of the clinical trial GESS (NCT03150680) is referenced. The latter is presented in a manner to provide a direction for the improvement of the implementation of pharmacogenomics and precision cardiovascular medicine trials.
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Affiliation(s)
- Fani Chatzopoulou
- Laboratory of Microbiology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (F.C.); (A.P.); (D.C.)
- Labnet Laboratories, Department of Molecular Biology and Genetics, 54638 Thessaloniki, Greece
| | - Konstantinos A. Kyritsis
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (K.A.K.); (C.I.P.); (N.F.T.)
| | - Christos I. Papagiannopoulos
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (K.A.K.); (C.I.P.); (N.F.T.)
| | - Eleftheria Galatou
- Department of Life & Health Sciences, University of Nicosia, Nicosia 1700, Cyprus;
| | - Nikolaos Mittas
- Department of Chemistry, International Hellenic University, 65404 Kavala, Greece;
| | - Nikoleta F. Theodoroula
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (K.A.K.); (C.I.P.); (N.F.T.)
| | - Andreas S. Papazoglou
- 1st Cardiology Department, AHEPA University General Hospital of Thessaloniki, 54636 Thessaloniki, Greece; (A.S.P.); (E.K.); (G.S.)
| | - Efstratios Karagiannidis
- 1st Cardiology Department, AHEPA University General Hospital of Thessaloniki, 54636 Thessaloniki, Greece; (A.S.P.); (E.K.); (G.S.)
| | - Maria Chatzidimitriou
- Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece;
| | - Anna Papa
- Laboratory of Microbiology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (F.C.); (A.P.); (D.C.)
| | - Georgios Sianos
- 1st Cardiology Department, AHEPA University General Hospital of Thessaloniki, 54636 Thessaloniki, Greece; (A.S.P.); (E.K.); (G.S.)
| | - Lefteris Angelis
- Department of Informatics, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Dimitrios Chatzidimitriou
- Laboratory of Microbiology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (F.C.); (A.P.); (D.C.)
| | - Ioannis S. Vizirianakis
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (K.A.K.); (C.I.P.); (N.F.T.)
- Department of Life & Health Sciences, University of Nicosia, Nicosia 1700, Cyprus;
- Correspondence: or
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Guz M, Jeleniewicz W, Cybulski M. An Insight into miR-1290: An Oncogenic miRNA with Diagnostic Potential. Int J Mol Sci 2022; 23:1234. [PMID: 35163157 PMCID: PMC8835968 DOI: 10.3390/ijms23031234] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/12/2022] Open
Abstract
For more than two decades, the view of the roles of non-coding RNAs (ncRNAs) has been radically changing. These RNA molecules that are transcribed from our genome do not have the capacity to encode proteins, but are critical regulators of gene expression at different levels. Our knowledge is constantly enriched by new reports revealing the role of these new molecular players in the development of many pathological conditions, including cancer. One of the ncRNA classes includes short RNA molecules called microRNAs (miRNAs), which are involved in the post-transcriptional control of gene expression affecting various cellular processes. The aberrant expression of miRNAs with oncogenic and tumor-suppressive function is associated with cancer initiation, promotion, malignant transformation, progression and metastasis. Oncogenic miRNAs, also known as oncomirs, mediate the downregulation of tumor-suppressor genes and their expression is upregulated in cancer. Nowadays, miRNAs show promising application in diagnosis, prediction, disease monitoring and therapy response. Our review presents a current view of the oncogenic role of miR-1290 with emphasis on its properties as a cancer biomarker in clinical medicine.
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Affiliation(s)
- Małgorzata Guz
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland; (W.J.); (M.C.)
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18
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Rozhkova AV, Dmitrieva VG, Nosova EV, Dergunov AD, Limborska SA, Dergunova LV. Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis. J Cardiovasc Dev Dis 2021; 8:jcdd8120170. [PMID: 34940525 PMCID: PMC8707585 DOI: 10.3390/jcdd8120170] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.
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Affiliation(s)
- Alexandra V. Rozhkova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Veronika G. Dmitrieva
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Elena V. Nosova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Alexander D. Dergunov
- Laboratory of Structural Fundamentals of Lipoprotein Metabolism, National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia
- Correspondence:
| | - Svetlana A. Limborska
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
| | - Liudmila V. Dergunova
- Department of Molecular Bases of Human Genetics, Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia; (A.V.R.); (V.G.D.); (E.V.N.); (S.A.L.); (L.V.D.)
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Pinilla L, Benitez ID, González J, Torres G, Barbé F, de Gonzalo-Calvo D. Peripheral blood microRNAs and the COVID-19 patient: methodological considerations, technical challenges and practice points. RNA Biol 2021; 18:688-695. [PMID: 33530819 PMCID: PMC8078525 DOI: 10.1080/15476286.2021.1885188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/30/2021] [Indexed: 02/06/2023] Open
Abstract
The COVID-19 emergency pandemic resulting from infection with SARS-CoV-2 represents a major threat to public health worldwide. There is an urgent clinical demand for easily accessible tools to address weaknesses and gaps in the management of COVID-19 patients. In this context, transcriptomic profiling of liquid biopsies, especially microRNAs (miRNAs), has recently emerged as a robust source of potential clinical indicators for medical decision-making. Nevertheless, the analysis of the circulating miRNA signature and its translation to clinical practice requires strict control of a wide array of methodological details. In this review, we indicate the main methodological aspects that should be addressed when evaluating the circulating miRNA profiles in COVID-19 patients, from preanalytical and analytical variables to the experimental design, impact of confounding, analysis of the data and interpretation of the findings, among others. Additionally, we provide practice points to ensure the rigour and reproducibility of miRNA-based biomarker investigations of this condition.Abbreviations: ACE: angiotensin-converting enzyme; ARDS: acute respiratory distress syndrome; COVID-19: coronavirus disease 2019; ERDN: early Detection Research Network; LMWH: low molecular weight heparin; miRNA: microRNA; ncRNA: noncoding RNA; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2; SOP: standard operating procedure.
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Affiliation(s)
- Lucía Pinilla
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Ivan D. Benitez
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Jessica González
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Respiratory Department, University Hospital Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Gerard Torres
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- Respiratory Department, University Hospital Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Ferran Barbé
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Respiratory Department, University Hospital Arnau de Vilanova-Santa María, Translational Research in Respiratory Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
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Gutierrez-Carretero E, Mayoral-González I, Jesús Morón F, Fernández-Quero M, Domínguez-Rodríguez A, Ordóñez A, Smani T. miR-30b-5p Downregulation as a Predictive Biomarker of Coronary In-Stent Restenosis. Biomedicines 2021; 9:354. [PMID: 33808387 PMCID: PMC8066146 DOI: 10.3390/biomedicines9040354] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 03/26/2021] [Indexed: 12/15/2022] Open
Abstract
In-stent restenosis (ISR) is one of the main limitations of percutaneous coronary intervention (PCI) therapy with drug-eluting stents (DES) implantation. The aim of this study was to determine if circulating microRNAs (miRNAs) have diagnostic capability for determining ISR in a cohort of matched patients. Blood samples were collected from 55 patients who underwent previously PCI and were readmitted for a new coronary angiography. Patients were divided into subgroups comprising patients who presented ISR or not (non-ISR). A microarray analysis determined that up to 49 miRNAs were differentially expressed between ISR and non-ISR patients. Of these, 10 miRNAs are related to vascular smooth muscle and endothelial cells proliferation, migration, and differentiation, well-known hallmarks of vascular remodeling. Additionally, we identified that the expression of miR-30b-5p is significantly lower in serum samples of ISR patients, as compared to non-ISR. A further analysis demonstrated that miR-30b-5p provides better values of the receiver operator characteristic curve than other miRNAs and biochemical parameters. Finally, the in-silico analysis suggests that miR-30b-5p is predicted to target 62 genes involved in different signaling pathways involved in vascular remodeling. In conclusion, we determined for the first time that circulating mi-R30b-5p can reliably prognose restenosis in patient with implanted DES, which could be potentially helpful in the establishment of an early diagnosis and therapy of ISR.
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Affiliation(s)
- Encarnación Gutierrez-Carretero
- Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain; (E.G.-C.); (I.M.-G.); (A.D.-R.); (A.O.)
- Department of Surgery, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain
- University Hospital Virgen del Rocío, 41013 Sevilla, Spain;
| | - Isabel Mayoral-González
- Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain; (E.G.-C.); (I.M.-G.); (A.D.-R.); (A.O.)
- Department of Surgery, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain
| | - Francisco Jesús Morón
- Genomic Facility, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain;
| | | | - Alejandro Domínguez-Rodríguez
- Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain; (E.G.-C.); (I.M.-G.); (A.D.-R.); (A.O.)
| | - Antonio Ordóñez
- Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain; (E.G.-C.); (I.M.-G.); (A.D.-R.); (A.O.)
- Department of Surgery, Faculty of Medicine, University of Seville, 41009 Sevilla, Spain
| | - Tarik Smani
- Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CSIC, 41013 Seville, Spain; (E.G.-C.); (I.M.-G.); (A.D.-R.); (A.O.)
- Department of Medical Physiology and Biophysics, Faculty of Medicine, University of Seville, 41009 Seville, Spain
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21
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Šatrauskienė A, Navickas R, Laucevičius A, Krilavičius T, Užupytė R, Zdanytė M, Ryliškytė L, Jucevičienė A, Holvoet P. Mir-1, miR-122, miR-132, and miR-133 Are Related to Subclinical Aortic Atherosclerosis Associated with Metabolic Syndrome. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18041483. [PMID: 33557426 PMCID: PMC7915826 DOI: 10.3390/ijerph18041483] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 01/08/2023]
Abstract
Previously, miR-1, miR-122, miR-126, miR-132, miR-133, and miR-370 were found to be related to coronary artery disease (CAD) progression. However, their relationship with subclinical atherosclerosis, especially in subjects with metabolic syndrome, is unknown. Therefore, our aim was to determine their relationship with arterial markers of subclinical atherosclerosis. Metabolic syndrome subjects (n = 182) with high cardiovascular risk but without overt cardiovascular disease (CVD) were recruited from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program. The ardio-ankle vascular index (CAVI), augmentation index normalized to a heart rate of 75 bpm (AIxHR75), aortic pulse wave velocity (AoPWV), and carotid artery stiffness were assessed. MicroRNAs (miRs) were analyzed in serum. Pearson correlation and a univariate linear regression t-test showed that miR-1, miR-133b, and miR-133a were negatively associated with CAVI mean, whereas miR-122 was positively associated. MiR-1, miR-133b and miR-133a, and miR-145 were negatively associated with AIxHR75. MiR-122 correlated negatively with AoPWV. In multivariate linear regression models, miR-133b and miR-122 predicted CAVImean, miR-133 predicted AIxHR75, and miR-122 predicted AoPWV. MiR-132 predicted right carotid artery stiffness, and miR-1 predicted left carotid artery stiffness. The addition of smoking to miR-133b and miR-122 enhanced the prediction of CAVI. Age and triglycerides enhanced the prediction of AoPWV by miR-122. A cluster of four miRs are related to subclinical atherosclerosis in subjects with metabolic syndrome. Combined, they may have a more substantial diagnostic or prognostic value than any single miR. Future follow-up studies are needed to establish their clinical relevance.
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Affiliation(s)
- Agnė Šatrauskienė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania; (A.Š.); (A.L.); (L.R.); (A.J.)
- Centre of Cardiology and Angiology, Vilnius University Hospital, Santaros Klinikos, 08410 Vilnius, Lithuania
| | - Rokas Navickas
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania; (A.Š.); (A.L.); (L.R.); (A.J.)
- Centre of Cardiology and Angiology, Vilnius University Hospital, Santaros Klinikos, 08410 Vilnius, Lithuania
- Correspondence:
| | - Aleksandras Laucevičius
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania; (A.Š.); (A.L.); (L.R.); (A.J.)
- Centre of Cardiology and Angiology, Vilnius University Hospital, Santaros Klinikos, 08410 Vilnius, Lithuania
- Experimental, Preventive, and Clinic Medicine Department, Centre for Innovative Medicine, 08406 Vilnius, Lithuania
| | - Tomas Krilavičius
- Informatics Faculty, Vytautas Magnus University, 44248 Kaunas, Lithuania; (T.K.); (R.U.)
- Baltic Institute of Advanced Technology, 01124 Vilnius, Lithuania
| | - Rūta Užupytė
- Informatics Faculty, Vytautas Magnus University, 44248 Kaunas, Lithuania; (T.K.); (R.U.)
- Baltic Institute of Advanced Technology, 01124 Vilnius, Lithuania
- Faculty of Mathematics and Informatics, Vilnius University, 03225 Vilnius, Lithuania
| | - Monika Zdanytė
- Department of Cardiology and Cardiovascular Medicine, Universität Tübingen, 72074 Tübingen, Germany;
| | - Ligita Ryliškytė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania; (A.Š.); (A.L.); (L.R.); (A.J.)
- Centre of Cardiology and Angiology, Vilnius University Hospital, Santaros Klinikos, 08410 Vilnius, Lithuania
| | - Agnė Jucevičienė
- Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania; (A.Š.); (A.L.); (L.R.); (A.J.)
- Centre of Cardiology and Angiology, Vilnius University Hospital, Santaros Klinikos, 08410 Vilnius, Lithuania
| | - Paul Holvoet
- Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium;
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22
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Kibel A, Lukinac AM, Dambic V, Juric I, Selthofer-Relatic K. Oxidative Stress in Ischemic Heart Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6627144. [PMID: 33456670 PMCID: PMC7785350 DOI: 10.1155/2020/6627144] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 11/27/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
One of the novel interesting topics in the study of cardiovascular disease is the role of the oxidation system, since inflammation and oxidative stress are known to lead to cardiovascular diseases, their progression and complications. During decades of research, many complex interactions between agents of oxidative stress, oxidation, and antioxidant systems have been elucidated, and numerous important pathophysiological links to na number of disorders and diseases have been established. This review article will present the most relevant knowledge linking oxidative stress to vascular dysfunction and disease. The review will focus on the role of oxidative stress in endotheleial dysfunction, atherosclerosis, and other pathogenetic processes and mechanisms that contribute to the development of ischemic heart disease.
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Affiliation(s)
- Aleksandar Kibel
- Department for Heart and Vascular Diseases, Osijek University Hospital, Osijek, Croatia
- Department of Physiology and Immunology, Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia
| | - Ana Marija Lukinac
- Department of Rheumatology and Clinical Immunology, Osijek University Hospital, Osijek, Croatia
- Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia
| | - Vedran Dambic
- Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia
- Department for Emergency Medical Services of the Osijek-Baranja county, Osijek, Croatia
| | - Iva Juric
- Department for Heart and Vascular Diseases, Osijek University Hospital, Osijek, Croatia
- Department of Internal Medicine, Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia
| | - Kristina Selthofer-Relatic
- Department for Heart and Vascular Diseases, Osijek University Hospital, Osijek, Croatia
- Department of Internal Medicine, Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia
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23
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Tang Y, Shah TA, Yurkow EJ, Rogers MB. MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378. Physiol Genomics 2020; 52:517-529. [PMID: 32956022 DOI: 10.1152/physiolgenomics.00074.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Our goal was to elucidate microRNAs (miRNAs) that may repress the excess bone morphogenetic protein (BMP) signaling observed during pathological calcification in the Klotho mouse model of kidney disease. We hypothesized that restoring healthy levels of miRNAs that post-transcriptionally repress osteogenic calcific factors may decrease aortic calcification. Our relative abundance profiles of miRNAs in healthy aorta differ greatly from those in calcified mouse aorta. Many of these miRNAs are predicted to regulate proteins involved in BMP signaling and may control osteogenesis. Two differentially regulated miRNAs, miR-145 and miR-378, were selected based on three criteria: reduced levels in calcified aorta, the ability to target more than one protein in the BMP signaling pathway, and conservation of targeted sequences between humans and mice. Forced expression using a lentiviral vector demonstrated that restoring normal levels repressed the synthesis of BMP2 and other pro-osteogenic proteins and inhibited pathological aortic calcification in Klotho mice with renal insufficiency. This study identified miRNAs that may impact BMP signaling in both sexes and demonstrated the efficacy of selected miRNAs in reducing aortic calcification in vivo. Calcification of the aorta and the aortic valve resulting from abnormal osteogenesis is common in those with kidney disease, diabetes, and high cholesterol. Such vascular osteogenesis is a clinically significant feature. The calcification modulating miRNAs described here are candidates for biomarkers and "miRNA replacement therapies" in the context of chronic kidney disease and other pro-calcific conditions.
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Affiliation(s)
- Ying Tang
- Rutgers - New Jersey Medical School, Microbiology, Biochemistry, & Molecular Genetics, Newark, NJ, United States
| | - Tapan A Shah
- Rutgers - New Jersey Medical School, Microbiology, Biochemistry, & Molecular Genetics, Newark, NJ, United States
| | - Edward J Yurkow
- Rutgers University Molecular Imaging Center (RUMIC), Rutgers University, Piscataway, NJ, United States
| | - Melissa B Rogers
- Rutgers - New Jersey Medical School, Microbiology, Biochemistry, & Molecular Genetics, Newark, NJ, United States
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24
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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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25
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Gorabi AM, Kiaie N, Sathyapalan T, Al-Rasadi K, Jamialahmadi T, Sahebkar A. The Role of MicroRNAs in Regulating Cytokines and Growth Factors in Coronary Artery Disease: The Ins and Outs. J Immunol Res 2020; 2020:5193036. [PMID: 32775466 PMCID: PMC7397388 DOI: 10.1155/2020/5193036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/07/2020] [Accepted: 07/11/2020] [Indexed: 12/16/2022] Open
Abstract
Coronary artery diseases (CAD), as a leading cause of mortality around the world, has attracted the researchers' attention for years to find out its underlying mechanisms and causes. Among the various key players in the pathogenesis of CAD cytokines, microRNAs (miRNAs) are crucial. In this study, besides providing a comprehensive overview of the involvement of cytokines, growth factors, and miRNAs in CAD, the interplay between miRNA with cytokine or growth factors during the development of CAD is discussed.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Kiaie
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | | | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Fasolo F, Di Gregoli K, Maegdefessel L, Johnson JL. Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovasc Res 2020; 115:1732-1756. [PMID: 31389987 DOI: 10.1093/cvr/cvz203] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/14/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis underlies the predominant number of cardiovascular diseases and remains a leading cause of morbidity and mortality worldwide. The development, progression and formation of clinically relevant atherosclerotic plaques involves the interaction of distinct and over-lapping mechanisms which dictate the roles and actions of multiple resident and recruited cell types including endothelial cells, vascular smooth muscle cells, and monocyte/macrophages. The discovery of non-coding RNAs (ncRNAs) including microRNAs, long non-coding RNAs, and circular RNAs, and their identification as key mechanistic regulators of mRNA and protein expression has piqued interest in their potential contribution to atherosclerosis. Accruing evidence has revealed ncRNAs regulate pivotal cellular and molecular processes during all stages of atherosclerosis including cell invasion, growth, and survival; cellular uptake and efflux of lipids, expression and release of pro- and anti-inflammatory intermediaries, and proteolytic balance. The expression profile of ncRNAs within atherosclerotic lesions and the circulation have been determined with the aim of identifying individual or clusters of ncRNAs which may be viable therapeutic targets alongside deployment as biomarkers of atherosclerotic plaque progression. Consequently, numerous in vivo studies have been convened to determine the effects of moderating the function or expression of select ncRNAs in well-characterized animal models of atherosclerosis. Together, clinicopathological findings and studies in animal models have elucidated the multifaceted and frequently divergent effects ncRNAs impose both directly and indirectly on the formation and progression of atherosclerosis. From these findings' potential novel therapeutic targets and strategies have been discovered which may pave the way for further translational studies and possibly taken forward for clinical application.
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Affiliation(s)
- Francesca Fasolo
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar-Technical University Munich, Biedersteiner Strasse 29, Munich, Germany
| | - Karina Di Gregoli
- Laboratory of Cardiovascular Pathology, Bristol Medical School, University of Bristol, Bristol, UK
| | - Lars Maegdefessel
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar-Technical University Munich, Biedersteiner Strasse 29, Munich, Germany.,Molecular Vascular Medicine, Karolinska Institute, Center for Molecular Medicine L8:03, 17176 Stockholm, Sweden.,German Center for Cardiovascular Research (DZHK), Partner Site Munich (Munich Heart Alliance), Munich, Germany
| | - Jason L Johnson
- Laboratory of Cardiovascular Pathology, Bristol Medical School, University of Bristol, Bristol, UK
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27
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Zheng J, Wang W, Hong T, Yang S, Shen J, Liu C. Suppression of microRNA-155 exerts an anti-inflammatory effect on CD4+ T cell-mediated inflammatory response in the pathogenesis of atherosclerosis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:654-664. [PMID: 32372074 DOI: 10.1093/abbs/gmaa040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/27/2022] Open
Abstract
In the current study, we aimed to investigate the effects of miR-155 on CD4+ T cell-mediated immune response in the pathogenesis of atherosclerosis. CD34+ hematopoietic stem cells, CD4+ T lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) were harvested from the same donor. Knockdown of miR-155 in the CD4+ T cells was achieved by lentiviral transfection, whereas control RNA-transfected or untransfected lymphocytes were used as controls. The transfected CD4+ T cells were activated by incubating with oxidized low-density lipoprotein-treated dendritic cells. The proliferative capacities, phenotype distribution, and cytokine secretion profiles of the activated CD4+ T cells from different groups were evaluated. The activated lymphocytes were used to treat ECs co-cultivated with VSMCs. The ability of the CD4+ T cells to induce the apoptosis of the ECs and to promote the proliferation of the VSMCs was investigated. Inhibition of miR-155 was found to significantly reduce the proliferation rate of the transfected CD4+ T cells. CD4+ T lymphocytes transfected with the miR-155 inhibitor showed increased populations of T helper type 2 and regulatory T cells, as well as more production of anti-inflammatory cytokines. MiR-155 knockdown was also shown to significantly hamper the ability to CD4+ T cells to induce EC apoptosis and to promote the growth of VSMCs. Our data suggested that inhibition of miR-155 in CD4+ T cells could slow down the formation of atherosclerotic plaques. These results lay the groundwork for future research on the therapeutic potential of miR-155 against atherosclerosis-associated cardiovascular diseases.
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Affiliation(s)
- Jiayu Zheng
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenshuo Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Hong
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shouguo Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jinqiang Shen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chen Liu
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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28
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Su M, Niu Y, Dang Q, Qu J, Zhu D, Tang Z, Gou D. Circulating microRNA profiles based on direct S-Poly(T)Plus assay for detection of coronary heart disease. J Cell Mol Med 2020; 24:5984-5997. [PMID: 32343493 PMCID: PMC7294166 DOI: 10.1111/jcmm.15001] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 12/07/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Coronary heart disease (CHD) is one of the leading causes of heart-associated deaths worldwide. Conventional diagnostic techniques are ineffective and insufficient to diagnose CHD with higher accuracy. To use the circulating microRNAs (miRNAs) as non-invasive, specific and sensitive biomarkers for diagnosing of CHD, 203 patients with CHD and 144 age-matched controls (126 high-risk controls and 18 healthy volunteers) were enrolled in this study. The direct S-Poly(T)Plus method was used to identify novel miRNAs expression profile of CHD patients and to evaluate their clinical diagnostic value. This method is an RNA extraction-free and robust quantification method, which simplifies procedures, reduces variations, in particular increases the accuracy. Twelve differentially expressed miRNAs between CHD patients and high-risk controls were selected, and their performances were evaluated in validation set-1 with 96 plasma samples. Finally, six (miR-15b-5p, miR-29c-3p, miR-199a-3p, miR-320e, miR-361-5p and miR-378b) of these 12 miRNAs were verified in validation set-2 with a sensitivity of 92.8% and a specificity of 89.5%, and the AUC was 0.971 (95% confidence interval, 0.948-0.993, P < .001) in a large cohort for CHD patients diagnosis. Plasma fractionation indicated that only a small amount of miRNAs were assembled into EVs. Direct S-Poly(T)Plus method could be used for disease diagnosis and 12 unique miRNAs could be used for diagnosis of CHD.
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Affiliation(s)
- Mingyang Su
- Shenzhen Key Laboratory of Microbial Genetic EngineeringVascular Disease Research CenterCollege of Life Sciences and OceanographyGuangdong Provincial Key Laboratory of Regional Immunity and DiseasesCarson International Cancer CenterShenzhen UniversityShenzhenGuangdongChina
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong ProvinceCollege of Optoelectronic EngineeringShenzhen UniversityShenzhenGuangdongChina
| | - Yanqin Niu
- Shenzhen Key Laboratory of Microbial Genetic EngineeringVascular Disease Research CenterCollege of Life Sciences and OceanographyGuangdong Provincial Key Laboratory of Regional Immunity and DiseasesCarson International Cancer CenterShenzhen UniversityShenzhenGuangdongChina
| | - Quanjin Dang
- Shenzhen Key Laboratory of Microbial Genetic EngineeringVascular Disease Research CenterCollege of Life Sciences and OceanographyGuangdong Provincial Key Laboratory of Regional Immunity and DiseasesCarson International Cancer CenterShenzhen UniversityShenzhenGuangdongChina
| | - Junle Qu
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong ProvinceCollege of Optoelectronic EngineeringShenzhen UniversityShenzhenGuangdongChina
| | - Daling Zhu
- Department of Biopharmaceutical SciencesCollege of PharmacyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Zhongren Tang
- Third Cardiovascular DepartmentMudanjiang City Second People's HospitalMudanjiangHeilongjiangChina
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic EngineeringVascular Disease Research CenterCollege of Life Sciences and OceanographyGuangdong Provincial Key Laboratory of Regional Immunity and DiseasesCarson International Cancer CenterShenzhen UniversityShenzhenGuangdongChina
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29
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Barraclough JY, Joglekar MV, Januszewski AS, Martínez G, Celermajer DS, Keech AC, Hardikar AA, Patel S. A MicroRNA Signature in Acute Coronary Syndrome Patients and Modulation by Colchicine. J Cardiovasc Pharmacol Ther 2020; 25:444-455. [PMID: 32356454 DOI: 10.1177/1074248420922793] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. METHODS A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. RESULTS Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. CONCLUSION The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy.
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Affiliation(s)
- Jennifer Y Barraclough
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
| | - Mugdha V Joglekar
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Andrzej S Januszewski
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Gonzalo Martínez
- Heart Research Institute Sydney, Australia.,Division of Cardiovascular Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - David S Celermajer
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
| | - Anthony C Keech
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Anandwardhan A Hardikar
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Australia
| | - Sanjay Patel
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.,Sydney Medical School, The University of Sydney, Australia.,Heart Research Institute Sydney, Australia
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30
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Siasos G, Bletsa E, Stampouloglou PK, Oikonomou E, Tsigkou V, Paschou SA, Vlasis K, Marinos G, Vavuranakis M, Stefanadis C, Tousoulis D. MicroRNAs in cardiovascular disease. Hellenic J Cardiol 2020; 61:165-173. [PMID: 32305497 DOI: 10.1016/j.hjc.2020.03.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/08/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) remains the predominant cause of human morbidity and mortality in developed countries. Currently, microRNAs have been investigated in many diseases as well-promising biomarkers for diagnosis, prognosis, and disease monitoring. Plenty studies have been designed so as to elucidate the properties of microRNAs in the classification and risk stratification of patients with CVD and also to evaluate their potentials in individualized management and guide treatment decisions. Therefore, in this review article, we aimed to present the most recent data concerning the role of microRNAs as potential novel biomarkers for cardiovascular disease.
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Affiliation(s)
- Gerasimos Siasos
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Evanthia Bletsa
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Panagiota K Stampouloglou
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Evangelos Oikonomou
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Vasiliki Tsigkou
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Stavroula A Paschou
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Konstantinos Vlasis
- Department of Anatomy, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Marinos
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Manolis Vavuranakis
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Christodoulos Stefanadis
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitris Tousoulis
- Department of Cardiology, 'Hippokration' General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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31
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Platelet MicroRNA 365-3p Expression Correlates with High On-treatment Platelet Reactivity in Coronary Artery Disease Patients. Cardiovasc Drugs Ther 2020; 33:129-137. [PMID: 30783954 DOI: 10.1007/s10557-019-06855-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
PURPOSE The expression level of platelet microRNAs (miRNAs) correlates with heart disease and may be altered by antiplatelet therapy. This study aims to assess whether certain miRNAs are associated with treatment response by platelets in patients who received percutaneous coronary intervention and antiplatelet therapy. The dynamic expression of certain miRNAs in patients receiving different antiplatelet regimens was also investigated. METHODS Healthy subjects (N = 20) received no-stent or antiplatelet therapy (as control), and patients (N = 155) who underwent stent implant and received treatment regimens that included aspirin plus clopidogrel, ticagrelor, or cilostazol were included. The association of miR-96-5p, miR-495-3p, miR-107, miR-223-3p, miR-15a-5, miR-365-3p, and miR-339-3p levels with treatment response, SYNTAX score, and HTPR was determined. RESULTS Of the different treatment regimens, ticagrelor was the most efficacious. At 24 h following drug administration, ROC analysis revealed that miR-339-3p and miR-365-3p had the highest sensitivity (74.3% and 90.0%, respectively) and specificity (71.4% and 93.3%) for detecting HTPR compared with the five other miRNAs. The SYNTAX score positively correlated with miR-223-3p and miR-365-3p levels at 24 h (P ≤ 0.006) and with miR-365-3p levels 7 days following drug administration (P = 0.014). The expression of all three miRNAs reached the highest levels in hyperresponsive (P2Y12 reaction unit < 85) followed by hyporesponsive (P2Y12 reaction unit ≥ 208) and then normoreactive. The normoreactive value was very close to that of controls. CONCLUSIONS Our data suggest that miR-365-3p expression level correlates with the antiplatelet treatment response. CLINICAL TRIAL REGISTRATION NCT02101437.
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Felekkis K, Papaneophytou C. Challenges in Using Circulating Micro-RNAs as Biomarkers for Cardiovascular Diseases. Int J Mol Sci 2020; 21:ijms21020561. [PMID: 31952319 PMCID: PMC7013987 DOI: 10.3390/ijms21020561] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/12/2022] Open
Abstract
Micro-RNAs (miRNAs) play a pivotal role in the development and physiology of the cardiovascular system while they have been associated with multiple cardiovascular diseases (CVDs). Several cardiac miRNAs are detectable in circulation (circulating miRNAs; c-miRNAs) and are emerging as diagnostic and therapeutic biomarkers for CVDs. c-miRNAs exhibit numerous essential characteristics of biomarkers while they are extremely stable in circulation, their expression is tissue-/disease-specific, and they can be easily detected using sequence-specific amplification methods. These features of c-miRNAs are helpful in the development of non-invasive assays to monitor the progress of CVDs. Despite significant progress in the detection of c-miRNAs in serum and plasma, there are many contradictory publications on the alterations of cardiac c-miRNAs concentration in circulation. The aim of this review is to examine the pre-analytical and analytical factors affecting the quantification of c-miRNAs and provide general guidelines to increase the accuracy of the diagnostic tests in order to improve future research on cardiac c-miRNAs.
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Coban N, Pirim D, Erkan AF, Dogan B, Ekici B. Hsa-miR-584-5p as a novel candidate biomarker in Turkish men with severe coronary artery disease. Mol Biol Rep 2019; 47:1361-1369. [PMID: 31863331 DOI: 10.1007/s11033-019-05235-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/07/2019] [Indexed: 12/16/2022]
Abstract
Coronary artery disease (CAD) is still the preliminary cause of mortality and morbidity in the developed world. Identification of novel predictive and therapeutic biomarkers is crucial for accurate diagnosis, prognosis and treatment of the CAD. The aim of this study was to detect novel candidate miRNA biomarker that may be used in the management of CAD. We performed miRNA profiling in whole blood samples of angiographically confirmed Turkish men with CAD and non-CAD controls with insignificant coronary stenosis. Validation of microarray results was performed by qRT-PCR in a larger cohort of 62 samples. We subsequently assessed the diagnostic value of the miRNA and correlations of miRNA with clinical parameters. miRNA-target identification and network analyses were conducted by Ingenuity Pathway Analysis (IPA) software. Hsa-miR-584-5p was one of the top significantly dysregulated miRNA observed in miRNA microarray. Men-specific down-regulation (p = 0.040) of hsa-miR-584-5p was confirmed by qRT-PCR. ROC curve analysis highlighted the potential diagnostic value of hsa-miR-584-5p with a power area under the curve (AUC) of 0.714 and 0.643 in men and in total sample, respectively. The expression levels of hsa-miR-584-5p showed inverse correlation with stenosis and Gensini scores. IPA revealed CDH13 as the only CAD related predicted target for the miRNA with biological evidence of its involvement in CAD. This study suggests that hsa-miR-584-5p, known to be tumor suppressor miRNA, as a candidate biomarker for CAD and highlighted its putative role in the CAD pathogenesis. The validation of results in larger samples incorporating functional studies warrant further research.
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Affiliation(s)
- Neslihan Coban
- Department of Genetics, Aziz Sancar Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.
| | - Dilek Pirim
- Faculty of Arts & Science, Department of Molecular Biology and Genetics, Bursa Uludag University, Bursa, Turkey
| | - Aycan Fahri Erkan
- Faculty of Medicine, Department of Cardiology, Ufuk University, Ankara, Turkey
| | - Berkcan Dogan
- Institute of Graduate Studies in Sciences, Department of Molecular Biology and Genetics, Istanbul University, Istanbul, Turkey
- Department of Medical Genetics, Bursa Uludag University, Bursa, Turkey
| | - Berkay Ekici
- Faculty of Medicine, Department of Cardiology, Ufuk University, Ankara, Turkey
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Solly EL, Dimasi CG, Bursill CA, Psaltis PJ, Tan JTM. MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis. J Clin Med 2019; 8:E2199. [PMID: 31847094 PMCID: PMC6947565 DOI: 10.3390/jcm8122199] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 12/11/2019] [Indexed: 12/21/2022] Open
Abstract
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease.
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Affiliation(s)
- Emma L. Solly
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Catherine G. Dimasi
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
| | - Christina A. Bursill
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Peter J. Psaltis
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Joanne T. M. Tan
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
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Abstract
OBJECTIVE Individuals with HIV suffer a higher burden of cardiovascular diseases. Traditional cardiovascular risk scores consistently underestimate cardiovascular risk in this population. Subsets of microRNAs (miRNAs) are differentially expressed among individuals with cardiovascular disease and individuals infected with HIV. However, no study has clarified whether specific miRNAs may be biomarkers for cardiovascular disease in individuals with HIV. DESIGN/METHODS We compared the miRNA expression profiles of 34 HIV-positive individuals who had experienced clinically adjudicated type I myocardial infarctions (MI) with the profiles of 76 HIV-positive controls matched by traditional cardiovascular risk factors and HIV-specific measures. Using the elastic net algorithm, we selected miRNAs most strongly associated with incident MI and then used conditional Cox proportional hazards regression and cross-validation to evaluate miRNAs and their association with incident MI. We evaluated whether miRNA markers would improve risk classification relative to the Framingham Risk Score. RESULTS Higher miR-125a-5p and miR-139-5p expression levels were each associated with increased risk of developing MI after adjustment for Framingham Risk Score and HIV-related factors (hazard ratio 2.43, P = 0.018; hazard ratio 2.13, P = 0.048, respectively). Compared with the Framingham Risk Score alone, adding expression levels of miR-125a-5p or miR-139-5p resulted in an integrated discrimination improvement of 10.1 or 5.8%, respectively. CONCLUSION MiR-125a-5p and miR-139-5p, transcripts known to be differentially expressed in HIV-positive individuals, may serve as unique biomarkers predictive of cardiovascular disease in these patients and may help clarify processes because of HIV infection that contribute to cardiovascular disorders in this population.
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Sanlialp M, Dodurga Y, Uludag B, Alihanoglu YI, Enli Y, Secme M, Bostanci HE, Cetin Sanlialp S, Tok OO, Kaftan A, Kilic ID. Peripheral blood mononuclear cell microRNAs in coronary artery disease. J Cell Biochem 2019; 121:3005-3009. [PMID: 31788836 DOI: 10.1002/jcb.29557] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 10/04/2013] [Indexed: 11/11/2022]
Abstract
The accuracy of risk prediction for coronary artery disease can be improved with the use of novel molecular or genetic biomarkers. In this study, we investigated the difference of five selected microRNAs (miR or miRNA) in patients with coronary artery disease (CAD) and controls, assessed by coronary angiography. The study population consisted of 85 subjects, aged between 18 and 75 years and underwent invasive coronary angiography. Subjects with more than 30% stenosis in at least one coronary artery, patients with a history of prior percutaneous coronary intervention or coronary by-pass surgery were allocated to the patient group; whereas the subjects without at least 30% stenosis consisted the control group. Groups were similar in age, presence of hypertension, and smoking status. However, the proportion of males and subjects taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, nitrates, and statins were higher in the patient group. miR-221 and miR-155 were downregulated (P = .02 and .001, respectively), while miR-21 levels were significantly increased (P = .003) in the patient group compared to controls. Changes in miR-145 and miR-126 did not reach statistical significance (P > .05). miRNA- 21, miR-155, and miR-221 were differentially expressed between the patients and controls. miRNAs are promising biomarkers for CAD diagnosis, however, this requires further research with larger groups.
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Affiliation(s)
- Musa Sanlialp
- Department of Cardiology, Tavas State Hospital, Denizli, Turkey
| | - Yavuz Dodurga
- Department of Medical Biology and Genetics, School of Medicine, Pamukkale University, Denizli, Turkey
| | - Burcu Uludag
- Department of Cardiology, Dr. Suat Seren Chest Hospital, Izmir, Turkey
| | | | - Yasar Enli
- Department of Biochemistry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Mucahit Secme
- Department of Medical Biology and Genetics, School of Medicine, Pamukkale University, Denizli, Turkey
| | - Hayrani Eren Bostanci
- Department of Biochemistry, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | | | - Ozge Ozden Tok
- Department of Cardiology, Bahcelievler Memorial Hospital, Istanbul, Turkey
| | - Asuman Kaftan
- Department of Cardiology, Pamukkale University Hospital, Denizli, Turkey
| | - Ismail Dogu Kilic
- Department of Cardiology, Pamukkale University Hospital, Denizli, Turkey
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Kukava NG, Shkhnovich RM, Osmak GZ, Baulina NM, Matveeva NA, Favorova OO. [The Role of microRNA in the Development of Ischemic Heart Disease]. ACTA ACUST UNITED AC 2019; 59:78-87. [PMID: 31615390 DOI: 10.18087/cardio.2019.10.n558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 04/29/2019] [Indexed: 11/18/2022]
Abstract
Coronary artery disease is the most clinically significant manifestation of atherosclerosis and the main cause of morbidity and mortality around the world. Atherogenesis is a complex process, involving various types of cells and regulatory molecules. MicroRNA molecules were discovered at the end of the 20th century, and nowadays are the important regulators of several pathophysiological processes of atherogenesis. The review examines data on the participation of various microRNAs in the development of atherosclerosis and its main clinical manifestations and discusses the possibility of using microRNAs as diagnostic markers for these diseases.
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Affiliation(s)
- N G Kukava
- Institute of Clinical Cardiology named after A.L. Myasnikov, National Cardiology Research Center
| | - R M Shkhnovich
- Institute of Clinical Cardiology named after A.L. Myasnikov, National Cardiology Research Center; Medical Academy of Continuing Education Russian Medical Academy of Postgraduate Education
| | - G Z Osmak
- Institute of Experimental Cardiology, National Medical Research Center for Cardiology
| | - N M Baulina
- Institute of Experimental Cardiology, National Medical Research Center for Cardiology
| | - N A Matveeva
- Institute of Experimental Cardiology, National Medical Research Center for Cardiology
| | - O O Favorova
- Institute of Experimental Cardiology, National Medical Research Center for Cardiology
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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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Yuan L, Fan L, Li Q, Cui W, Wang X, Zhang Z. Inhibition of miR‐181b‐5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3. J Cell Biochem 2019; 120:19647-19659. [PMID: 31297863 DOI: 10.1002/jcb.29271] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 04/08/2019] [Indexed: 12/30/2022]
Affiliation(s)
- Limei Yuan
- College of Acupuncture and Message Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Lihua Fan
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Qinghai Li
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Wei Cui
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Xuechen Wang
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Zhiguo Zhang
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
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40
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Melak T, Baynes HW. Circulating microRNAs as possible biomarkers for coronary artery disease: a narrative review. EJIFCC 2019; 30:179-194. [PMID: 31263392 PMCID: PMC6599194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Coronary artery disease is one of the most common cardiovascular diseases in the world. Involvement of microRNAs on the pathogenesis of this disease was reported either in beneficial or detrimental way. Different studies have also speculated that circulating microRNAs can be applied as promising biomarkers for the diagnosis of coronary artery disease. Particularly, microRNA-133a seems to fulfill the criteria of ideal biomarkers due to its role in the diagnosis, severity assessment and in prognosis. The panel of circulating microRNAs has also improved the predictive power of coronary artery disease compared to single microRNAs. In this review, the role of circulating microRNAs for early detection, severity assessment and prognosis of coronary artery disease were reviewed.
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Affiliation(s)
- Tadele Melak
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Northwest Ethiopia, Ethiopia
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Circulating microRNA-378 levels serve as a novel biomarker for assessing the severity of coronary stenosis in patients with coronary artery disease. Biosci Rep 2019; 39:BSR20182016. [PMID: 31064817 PMCID: PMC6522732 DOI: 10.1042/bsr20182016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/05/2019] [Accepted: 05/02/2019] [Indexed: 01/22/2023] Open
Abstract
Background: Circulating microRNAs (miRNA) are steady preserved in blood plasma. Multiple evidences have shown that miRNAs play a crucial role in cardiovascular disease including miRNA-378, which has been illustrated to participate in diverse physiological and pathological processes of cardiovascular disease. In the present study, we aim to explore the expression of plasma miRNA-378 and its clinical significance in patients with coronary artery disease (CAD). Methods: MiRNA-378 expression in blood plasma was performed by quantitative real-time PCR (qRT-PCR) in 215 CAD patients and 52 matched controls of healthy populations. Medical information of all patients including the results of coronary angiography (CAG) was acquired through hospital information system (HIS). Spearman’s correlation, binary linear regression, and covariance analysis were used to examine the association between miRNA-378 and relative clinical risk factors. Receiver operating characteristic curve analysis was applied to evaluate the value of miRNA-378 in predicting the disease severity of coronary lesion. Results: Plasma miR-378 expression was significantly down-regulated in CAD patients compared with healthy controls. Relative miR-378 level was shown conversely correlated with Gensini score, which present the severity of coronary artery lesions. Moreover, it is indicated that miR-378 expression can effectively distinguish patients with or without coronary artery stenosis. Conclusions: Plasma miR-378 levels appear to be a promising non-invasive biomarker, but require to be further validated by a large cohort study in future.
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Hawkins PG, Sun Y, Dess RT, Jackson WC, Sun G, Bi N, Tewari M, Hayman JA, Kalemkerian GP, Gadgeel SM, Lawrence TS, Haken RKT, Matuszak MM, Kong FMS, Schipper MJ, Jolly S. Circulating microRNAs as biomarkers of radiation-induced cardiac toxicity in non-small-cell lung cancer. J Cancer Res Clin Oncol 2019; 145:1635-1643. [PMID: 30923943 DOI: 10.1007/s00432-019-02903-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 03/22/2019] [Indexed: 12/13/2022]
Abstract
PURPOSE Radiation-induced cardiac toxicity (RICT) is an increasingly well-appreciated source of morbidity and mortality in patients receiving thoracic radiotherapy (RT). Currently available methods to predict RICT are suboptimal. We investigated circulating microRNAs (c-miRNAs) as potential biomarkers of RICT in patients undergoing definitive RT for non-small-cell lung cancer (NSCLC). METHODS Data from 63 patients treated on institutional trials were analyzed. Prognostic models of grade 3 or greater (G3 +) RICT based on pre-treatment c-miRNA levels ('c-miRNA'), mean heart dose (MHD) and pre-existing cardiac disease (PCD) ('clinical'), and a combination of these ('c-miRNA + clinical') were developed. Elastic net Cox regression and full cross validation were used for variable selection, model building, and model evaluation. Concordance statistic (c-index) and integrated Brier score (IBS) were used to evaluate model performance. RESULTS MHD, PCD, and serum levels of 14 c-miRNA species were identified as jointly prognostic for G3 + RICT. The 'c-miRNA and 'clinical' models yielded similar cross-validated c-indices (0.70 and 0.72, respectively) and IBSs (0.26 and 0.28, respectively). However, prognostication was not improved by combining c-miRNA and clinical factors (c-index 0.70, IBS 0.28). The 'c-miRNA' and 'clinical' models were able to significantly stratify patients into high- and low-risk groups of developing G3 + RICT. Chi-square testing demonstrated a marginally significantly higher prevalence of PCD in patients with high- compared to low-risk c-miRNA profile (p = 0.09), suggesting an association between some c-miRNAs and PCD. CONCLUSIONS We identified a pre-treatment c-miRNA signature prognostic for G3 + RICT. With further development, pre- and mid-treatment c-miRNA profiling could contribute to patient-specific dose selection and treatment adaptation.
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Affiliation(s)
- Peter G Hawkins
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Yilun Sun
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Robert T Dess
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - William C Jackson
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Grace Sun
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Nan Bi
- Department of Radiation Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Muneesh Tewari
- Department of Biomedical Engineering, Biointerfaces Institute, and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - James A Hayman
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Gregory P Kalemkerian
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Shirish M Gadgeel
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Randall K Ten Haken
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Martha M Matuszak
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
| | - Feng-Ming Spring Kong
- Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Matthew J Schipper
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Shruti Jolly
- Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Drive, UH B2 C490 SPC 5010, Ann Arbor, MI, 48109, USA.
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Xue S, Liu D, Zhu W, Su Z, Zhang L, Zhou C, Li P. Circulating MiR-17-5p, MiR-126-5p and MiR-145-3p Are Novel Biomarkers for Diagnosis of Acute Myocardial Infarction. Front Physiol 2019; 10:123. [PMID: 30833907 PMCID: PMC6387945 DOI: 10.3389/fphys.2019.00123] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/31/2019] [Indexed: 12/15/2022] Open
Abstract
Ischemic heart disease including myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. In order to manage the acute myocardial infarction (AMI) outbreaks, novel biomarkers for risk prediction are needed. Recent studies have shown that circulating microRNAs (miRNAs) are promising biomarkers for cardiovascular diseases prediction. This study aimed to determine the possibility of circulating miRNAs used as biomarkers for AMI. The dynamic expression levels of miRNAs were examined before and after percutaneous coronary intervention (PCI) in patients. Circulating miR-17-5p, miR-126-5p, and miR-145-3p were selected and validated in 29 patients with AMI and 21 matched controls by quantitative real-time PCR. The expression levels of plasma miR-17-5p, miR-126-5p, and miR-145-3p were significantly increased in AMI patients. Receiver Operating Characteristic (ROC) analysis indicated that miR-17-5p, miR-126-5p, and miR-145-3p showed considerable diagnostic efficiency for AMI. Furthermore, we demonstrated that the combination of these three miRNAs managed to provide more accurate diagnosing of AMI.
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Affiliation(s)
- Sheng Xue
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China
| | - Dacheng Liu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wenjie Zhu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Zhe Su
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Liwei Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Changyong Zhou
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China
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Ren F, Gao WC, Ke ZP, Xu Y, Liu Y. Identification of six miRNAs serving as predictive biomarkers in coronary artery disease. J Cell Biochem 2019; 120:1932-1942. [PMID: 30362594 DOI: 10.1002/jcb.27476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/25/2018] [Indexed: 01/24/2023]
Abstract
Coronary artery disease (CAD) is quite a common disease with high risk. It was reported that microRNAs (miRNAs) had significant effect on the occurrence of CAD. The previously published results are inconsistent due to the parameters, such as sequencing platform, samples selection, and the filter conditions. Here we aimed to explore the critical miRNAs in the occurrence of CAD, which may function as the potential biomarkers. A total of 12 representative datasets of miRNAs related to the occurrence of miRNAs were finally selected, and the critical miRNAs were determined by the comparison of the overlap relations. TargetScan software was used to predict the target genes of these critical miRNAs. Besides, DAVID and Tfacts dataset were used to analyze the functional enrichment and the transcriptional factors analysis. At last, a total of six signature miRNAs were identified, among which five were significantly upregulated and one was downregulated. The target gene of upregulated miRNAs was mostly enriched in the process of RNA Polymerase II promoter and the transcription of DNA template, whereas the target genes of downregulated miRNAs were mostly enriched in the regulation of transcription, DNA-templated. Besides, the result of the transcriptional factor analysis showed that there were 43 factors coexisting in two kinds of target genes. In summary, six critical miRNAs, as well as the corresponding target genes and transcriptional factors, were identified in the occurrence of CAD by bioinformatics analysis. These identified miRNAs may function as potential biomarkers in the clinical management of CAD.
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Affiliation(s)
- Fei Ren
- Department of Cardiology, The First People's Hospital of Jingmen, Jingmen, China
| | - Wen-Chuang Gao
- Department of Thoracic Surgery, Lian Shui People's Hospital, Huai'an, China
| | - Zun-Ping Ke
- Department of Cardiology, The Fifth People's Hospital of Shanghai, Shanghai, China
| | - Yong Xu
- Department of Nephrology, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huaian Shi, China
| | - Yu Liu
- Department of Cardiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China
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Altamemi IAM, Hassan AR, Jawad A. miRNA-1, miRNA-145 as a Myocardial Infarction Diagnostic Biomarker. ACTA ACUST UNITED AC 2018. [DOI: 10.13005/bbra/2712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Many myocardial infarction biomarkers currently available but they are a lack of specificity, therefore present study suggests to evaluate the significant importance of miRNA-1, miRNA-145 as biomarkers for early diagnosis of myocardial infarction. A blood sample was collected from three groups. The first group was patients with acute myocardial infarction (MI), the Second group was patients who have a risk factor for MI, and the Third group included healthy volunteers. Serum blood of this sample used to RNA purification and cDNA application with stem-loop specific primer then miRNA-1, and miRNA-145 was quantitated by using RT-PCR. The level of miR-1 fold change was significantly highest in the MI group followed by risk group and then by control group (P<0.05). while of miRNA-145 fold change was significantly lowest in the MI group followed by risk group and then by control group (P<0.05). A receiver operator characteristic (ROC) analysis; the cut off value was identified at miRNA-1 of >5.28 fold change with a sensitivity of 91.67 % and a specificity of 90.7%, while the cut off value of miRNA-145 has cut off ≤ 0.7 fold change with a sensitivity of 95.83 % and a specificity of 89.47%. miRNA-1, miR145 has high sensitivity and Specificity in this study which was bushed to using them as an alone biomarker or supported for Another biomarker in AMI diagnosis.
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Affiliation(s)
| | | | - Alawi Jawad
- M. B. CH. B Resident Physician at Al-Dewaniyah Teaching Hospital
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Reddy LL, Shah SAV, Ponde CK, Rajani RM, Ashavaid TF. Circulating miRNA-33: a potential biomarker in patients with coronary artery disease. Biomarkers 2018; 24:36-42. [PMID: 30022694 DOI: 10.1080/1354750x.2018.1501760] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND Circulating microRNAs (miRNA) are present in body fluids in stable, cell-free form. Likewise, these miRNAs can be identified in various stages of coronary artery disease (CAD) such as inflammation, endothelial dysfunction, proliferation and atherosclerosis among others. miRNA expression levels can be identified. AIMS AND OBJECTIVES To determine the expression of circulating miRNAs (miR-126, miR-92, miR-33, miR-145 and miR-155) in CAD patients of Indian origin. MATERIAL AND METHODS miRNA profiling analysis in blood plasma was performed by quantitative real-time-PCR (qRT-PCR) in 60 angiographically verified subjects including 30 CAD patients and 30 age- and gender-matched controls. Association between the expression of all five circulating miRNAs and clinical characteristics of patients with CAD were analysed using Medcalc statistics. The severity of CAD was assessed using SYNTAX score (SS). RESULTS Expression of plasma miR-33 increased by 2.9 folds in CAD patients than in control group (p value ≥0.002) also it was found that miR-33 expression levels in mild cases (SS: ≤22) were significantly higher than CAD controls. There was a modest negative correlation between miR-33 and total cholesterol/high density lipoprotein ratio, triglycerides and very low density lipoprotein. CONCLUSION The study reports a significant association between increased levels of plasma miR-33 and CAD. Thus, plasma miR-33 appears to be a promising non-invasive biomarker, but requires further validation in a large cohort.
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Affiliation(s)
- Lakshmi Lavanya Reddy
- a Research Laboratories Department , P. D. Hinduja Hospital and Medical Research Centre , Mahim, Mumbai , India
| | - Swarup A V Shah
- b Department of Laboratory Medicine , P. D. Hinduja Hospital and Medical Research Centre , Mahim, Mumbai , India
| | - Chandrashekhar K Ponde
- c Department of Cardiology , P. D. Hinduja Hospital and Medical Research Centre , Mahim, Mumbai , India
| | - Rajesh M Rajani
- c Department of Cardiology , P. D. Hinduja Hospital and Medical Research Centre , Mahim, Mumbai , India
| | - Tester F Ashavaid
- d Department of Lab Medicine , P. D. Hinduja Hospital and Medical Research Centre , Mahim, Mumbai , India
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MicroRNAs as Diagnostic and Prognostic Biomarkers in Ischemic Stroke-A Comprehensive Review and Bioinformatic Analysis. Cells 2018; 7:cells7120249. [PMID: 30563269 PMCID: PMC6316722 DOI: 10.3390/cells7120249] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/01/2018] [Accepted: 12/02/2018] [Indexed: 12/14/2022] Open
Abstract
Stroke is the second-most common cause of death worldwide. The pathophysiology of ischemic stroke (IS) is related to inflammation, atherosclerosis, blood coagulation, and platelet activation. MicroRNAs (miRNAs) play important roles in physiological and pathological processes of neurodegenerative diseases and progression of certain neurological diseases, such as IS. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of IS. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique value as diagnostic and prognostic markers in IS. In this review, we focus on the role of miRNAs as diagnostic and prognostic biomarkers in IS. We discuss the most common and reliable detection methods available and promising tests currently under development. We also present original results from bioinformatic analyses of published results, identifying the ten most significant genes (HMGB1, YWHAZ, PIK3R1, STAT3, MAPK1, CBX5, CAPZB, THBS1, TNFRSF10B, RCOR1) associated with inflammation, blood coagulation, and platelet activation and targeted by miRNAs in IS. Additionally, we created miRNA-gene target interaction networks based on Gene Ontology (GO) information derived from publicly available databases. Among our most interesting findings, miR-19a-3p is the most widely modulated miRNA across all selected ontologies and might be proposed as novel biomarker in IS to be tested in future studies.
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Johnson JL. Elucidating the contributory role of microRNA to cardiovascular diseases (a review). Vascul Pharmacol 2018; 114:31-48. [PMID: 30389614 PMCID: PMC6445803 DOI: 10.1016/j.vph.2018.10.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/13/2018] [Accepted: 10/28/2018] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases encompassing atherosclerosis, aortic aneurysms, restenosis, and pulmonary arterial hypertension, remain the leading cause of morbidity and mortality worldwide. In response to a range of stimuli, the dynamic interplay between biochemical and biomechanical mechanisms affect the behaviour and function of multiple cell types, driving the development and progression of cardiovascular diseases. Accumulating evidence has highlighted microRNAs (miRs) as significant regulators and micro-managers of key cellular and molecular pathophysiological processes involved in predominant cardiovascular diseases, including cell mitosis, motility and viability, lipid metabolism, generation of inflammatory mediators, and dysregulated proteolysis. Human pathological and clinical studies have aimed to identify select microRNA which may serve as biomarkers of disease and their progression, which are discussed within this review. In addition, I provide comprehensive coverage of in vivo investigations elucidating the modulation of distinct microRNA on the pathophysiology of atherosclerosis, abdominal aortic aneurysms, restenosis, and pulmonary arterial hypertension. Collectively, clinical and animal studies have begun to unravel the complex and often diverse effects microRNAs and their targets impart during the development of cardiovascular diseases and revealed promising therapeutic strategies through which modulation of microRNA function may be applied clinically.
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Affiliation(s)
- Jason L Johnson
- Laboratory of Cardiovascular Pathology, Bristol Medical School, University of Bristol, UK.
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Donaldson CJ, Lao KH, Zeng L. The salient role of microRNAs in atherogenesis. J Mol Cell Cardiol 2018; 122:98-113. [DOI: 10.1016/j.yjmcc.2018.08.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 08/05/2018] [Accepted: 08/06/2018] [Indexed: 12/17/2022]
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50
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Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, Leistner DM, Jakob P, Nakagawa S, Blankenberg S, Engelhardt S, Thum T, Weber C, Meder B, Hajjar R, Landmesser U. Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J 2018; 39:2704-2716. [PMID: 28430919 PMCID: PMC6454570 DOI: 10.1093/eurheartj/ehx165] [Citation(s) in RCA: 311] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 01/14/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.
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Affiliation(s)
- Wolfgang Poller
- Department of Cardiology, CBF, CC11, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Charite Centrum 11 (Cardiovascular Medicine), Hindenburgdamm 20, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Site Berlin, Berlin, Germany
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, Frankfurt am Main, Germany
- DZHK, Site Rhein-Main, Frankfurt, Germany
| | - Stephane Heymans
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Tanja Zeller
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistrasse 52, Hamburg, Germany
- DZHK, Site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Jan Haas
- Institute for Cardiomyopathies Heidelberg (ICH), Universitätsklinikum Heidelberg, Im Neuenheimer Feld 669, Heidelberg, Germany
- DZHK, Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Mahir Karakas
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistrasse 52, Hamburg, Germany
- DZHK, Site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - David-Manuel Leistner
- Department of Cardiology, CBF, CC11, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Charite Centrum 11 (Cardiovascular Medicine), Hindenburgdamm 20, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Site Berlin, Berlin, Germany
| | - Philipp Jakob
- Department of Cardiology, CBF, CC11, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Charite Centrum 11 (Cardiovascular Medicine), Hindenburgdamm 20, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Site Berlin, Berlin, Germany
| | - Shinichi Nakagawa
- RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama, Japan
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo, Japan
| | - Stefan Blankenberg
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistrasse 52, Hamburg, Germany
- DZHK, Site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Stefan Engelhardt
- Institute for Pharmacology and Toxikology, Technische Universität München, Biedersteiner Strasse 29, München, Germany
- DZHK, Site Munich, Munich, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Christian Weber
- DZHK, Site Munich, Munich, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Pettenkoferstrasse 8a/9, Munich, Germany
| | - Benjamin Meder
- Institute for Cardiomyopathies Heidelberg (ICH), Universitätsklinikum Heidelberg, Im Neuenheimer Feld 669, Heidelberg, Germany
- DZHK, Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Roger Hajjar
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ulf Landmesser
- Department of Cardiology, CBF, CC11, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Charite Centrum 11 (Cardiovascular Medicine), Hindenburgdamm 20, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Site Berlin, Berlin, Germany
- Berlin Institute of Health, Kapelle-Ufer 2, Berlin, Germany
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