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Ren X, Ellis BW, Ronan G, Blood SR, DeShetler C, Senapati S, March KL, Handberg E, Anderson D, Pepine C, Chang HC, Zorlutuna P. A multiplexed ion-exchange membrane-based miRNA (MIX·miR) detection platform for rapid diagnosis of myocardial infarction. LAB ON A CHIP 2021; 21:3876-3887. [PMID: 34546237 PMCID: PMC9115728 DOI: 10.1039/d1lc00685a] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Micro RNAs (miRNAs) have shown great potential as rapid and discriminating biomarkers for acute myocardial infarction (AMI) diagnosis. We have developed a multiplexed ion-exchange membrane-based miRNA (MIX·miR) preconcentration/sensing amplification-free platform for quantifying in parallel a panel of miRNAs, including miR-1, miR-208b, and miR-499, from the same plasma samples from: 1) reference subjects with no evident coronary artery disease (NCAD); 2) subjects with stable coronary artery disease (CAD); and 3) subjects experiencing ST-elevation myocardial infarction (STEMI) prior to (STEMI-pre) and following (STEMI-PCI) percutaneous coronary intervention. The picomolar limit of detection from raw plasma and 3-decade dynamic range of MIX·miR permits detection of the miRNA panel in untreated samples from disease patients and its precise standard curve, provided by large 0.1 to 1 V signals and eliminates individual sensor calibration. The use of molecular concentration feature reduces the assay time to less than 30 minutes and increases the detection sensitivity by bringing all targets close to the sensors. miR-1 was low for NCAD patients but more than one order of magnitude above the normal value for all samples from three categories (CAD, STEMI-pre, and STEMI-PCI) of patients with CAD. In fact, miR-1 expression levels of stable CAD, STEMI-pre and STEMI-PCI are each more than 10-fold higher than the previous class, in that order, well above the 95% confidence level of MIX·miR. Its overexpression estimate is significantly higher than the PCR benchmark. This suggests that, in contrast to protein biomarkers of myocardial injury, miR-1 appears to differentiate ischemia from both reperfusion injury and non-AMI CAD patients. The battery-operated MIX·miR can be a portable and low-cost AMI diagnostic device, particularly useful in settings where cardiac catheterization is not readily available to determine the status of coronary reperfusion.
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Affiliation(s)
- Xiang Ren
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Bradley W Ellis
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - George Ronan
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
| | - Stuart Ryan Blood
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Cameron DeShetler
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Satyajyoti Senapati
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Keith L March
- Division of Cardiology, Department of Medicine in the College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Eileen Handberg
- Division of Cardiology, Department of Medicine in the College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - David Anderson
- Division of Cardiology, Department of Medicine in the College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Carl Pepine
- Division of Cardiology, Department of Medicine in the College of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Hsueh-Chia Chang
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Pinar Zorlutuna
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
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Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the p53/JMY Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5529430. [PMID: 34326916 PMCID: PMC8302385 DOI: 10.1155/2021/5529430] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/08/2021] [Accepted: 06/22/2021] [Indexed: 12/19/2022]
Abstract
Accumulating evidence has shown that endothelial progenitor cell-derived exosomes (EPC-Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC-Exos-derived microRNAs (miRNAs) on myocardial infarction (MI). A miRNA-Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the miRNA expression indicated by miRNA-Seq. Immunofluorescence, cell proliferation, and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro. Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT-PCR, and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA-mediated effects on MI. miR-363-3p and miR-218-5p were enriched in EPC-Exos, and miR-218-5p and miR-363-3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR-218-5p and miR-363-3p regulated p53 and junction-mediating and regulatory protein (JMY) by binding to the promoter region of p53 and the 3′ untranslated region of JMY. Additionally, treatment of CFs with Exo-miR-218-5p or Exo-miR-363-3p upregulated p53 and downregulated JMY expression, promoted mesenchymal-endothelial transition, and inhibited myocardial fibrosis. Administration of exosomes containing miR-218-5p mimic or miR-363-3p mimic ameliorated left coronary artery ligation-induced MI and restored myocardial tissue integrity in the MI model rats. In summary, these results show that the protective ability of EPC-Exos against MI was mediated by the shuttled miR-218-5p or miR-363-3p via targeting of the p53/JMY signaling pathway.
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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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Pedretti S, Brulhart-Meynet MC, Montecucco F, Lecour S, James RW, Frias MA. HDL protects against myocardial ischemia reperfusion injury via miR-34b and miR-337 expression which requires STAT3. PLoS One 2019; 14:e0218432. [PMID: 31220137 PMCID: PMC6586303 DOI: 10.1371/journal.pone.0218432] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 06/03/2019] [Indexed: 12/17/2022] Open
Abstract
PURPOSE High density lipoprotein (HDL) protects against myocardial infarction via mechanisms that remain unclear. STAT3 (signal transducer and activator of transcription 3) plays a key role in HDL-induced cardioprotection. In the heart, microRNAs (miRNAs) are involved in ischemia reperfusion injury. We therefore investigated whether the cardioprotective effect of HDL modulates miRNAs as a downstream target of STAT3 activation. METHODS STAT3 cardiomyocyte deficient mice (STAT3-KO) and wildtype littermates (STAT3-WT) were submitted to left coronary ligature and reperfused (IR) with or without injection of HDL. Infarct size (IS) was determined and cardiac miRNA expression was evaluated after reperfusion in sham, IR and IR+HDL hearts by microarray analysis. In vitro, neonatal rat ventricular cardiomyocytes were submitted to hypoxia with or without HDL incubation. Cell viability and miRNA expression were analysed. RESULTS In vivo, HDL reduced IS from 40.5±4.3% to 24.4±2.1% (p<0.05) in STAT3-WT mice. HDL failed to protect in STAT3-KO mice. In STAT3-WT mice, both miR-34b and miR-337 were increased in IR compared to sham and IR+HDL groups (p<0.05). These miRNAs were not modulated in STAT3-KO mice. In vitro, incubation with HDL improved cell viability against hypoxia (p<0.05). The expression of miR-34b and miR-337 was increased by hypoxia and reduced by HDL treatment (p<0.05). In cardiomyocytes transfected with miRNA mimics, HDL failed to improve cell viability against hypoxia. CONCLUSIONS Our study, performed both in vivo and in vitro, delineates a novel cardioprotective signalling pathway activated by HDL, involving STAT3-mediated decrease of miR-34b and miR-337 expression.
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Affiliation(s)
- Sarah Pedretti
- Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva, Switzerland
| | - Marie-Claude Brulhart-Meynet
- Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva, Switzerland
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy
- IRCCS AOU San Martino—IST, Genoa, Genoa, Italy
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Sandrine Lecour
- Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Richard W. James
- Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva, Switzerland
| | - Miguel A. Frias
- Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva, Switzerland
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Geneva, Switzerland
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MicroRNA-148b-3p is involved in regulating hypoxia/reoxygenation-induced injury of cardiomyocytes in vitro through modulating SIRT7/p53 signaling. Chem Biol Interact 2018; 296:211-219. [DOI: 10.1016/j.cbi.2018.10.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 09/26/2018] [Accepted: 10/08/2018] [Indexed: 12/21/2022]
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Feng Y, Zou L, Yan D, Chen H, Xu G, Jian W, Cui P, Chao W. Extracellular MicroRNAs Induce Potent Innate Immune Responses via TLR7/MyD88-Dependent Mechanisms. THE JOURNAL OF IMMUNOLOGY 2017; 199:2106-2117. [PMID: 28768728 DOI: 10.4049/jimmunol.1700730] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
Tissue ischemia, such as transient myocardial ischemia, leads to release of cellular RNA including microRNA(miRNA) into the circulation and extracellular (ex-) space, but the biological function of the ex-RNA is poorly understood. We recently reported that cardiac RNA of both human and rodent origins induced cytokine production and immune cell activation. However, the identity of the ex-RNA responsible for the proinflammatory effect remains unclear. In the current study, using an miRNA array, we profiled the plasma miRNAs 4 h after transient myocardial ischemia (45 min) or sham procedure. Among 38 plasma miRNAs that were elevated following ischemia, eight were tested for their ability to induce cytokine response in macrophages and cardiomyocytes. We found that six miRNA mimics (miR-34a, -122, -133a, -142, -146a, and -208a) induced cytokine production in a dose-dependent manner. The effects of miRNAs (miR-133a, -146a, and -208a) were diminished by uridine→adenosine mutation and by RNase pretreatment. The miRNA-induced cytokine (MIP-2, TNF-α, and IL-6) production was abolished in cells deficient of TLR7 or MyD88, or by a TLR7 antagonist, but remained the same in TLR3- or Trif-deficient cells. In vivo, mice i.p. injected with miR-133a or miR-146a had marked peritoneal neutrophil and monocyte migration, which was significantly attenuated in TLR7-/- mice. Moreover, locked nucleic acid anti-miRNA inhibitors of these six miRNAs markedly reduced cardiac RNA-induced cytokine production. Taken together, these data demonstrate that ex-miRNA mimics (miR-34a, -122, -133a, -142, -146a, and -208a) are potent innate immune activators and that the miRNAs most likely induce cytokine production and leukocyte migration through TLR7 signaling.
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Affiliation(s)
- Yan Feng
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and .,Department of Anesthesiology, Shock Trauma Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Lin Zou
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and.,Department of Anesthesiology, Shock Trauma Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Dan Yan
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and
| | - Hongliang Chen
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and
| | - Ganqiong Xu
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and
| | - Wenling Jian
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and
| | - Ping Cui
- Department of Anesthesiology, Shock Trauma Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Wei Chao
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144; and .,Department of Anesthesiology, Shock Trauma Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201
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MiR-320a as a Potential Novel Circulating Biomarker of Arrhythmogenic CardioMyopathy. Sci Rep 2017; 7:4802. [PMID: 28684747 PMCID: PMC5500514 DOI: 10.1038/s41598-017-05001-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 05/23/2017] [Indexed: 12/21/2022] Open
Abstract
Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p < 0.01). A similar trend was observed when comparing ACM (n = 13) and HC (n = 17) with athletic lifestyle, a ACM precipitating factor. Importantly, ACM patients miR-320a showed 0.78 ± 0.05 fold expression change vs. IVT (p = 0.03). When compared to non-invasive ACM diagnostic parameters, miR-320a ranked highly in discriminating ACM vs. IVT and it increased their accuracy. Finally, miR-320a expression did not correlate with ACM severity. Our data suggest that miR-320a may be considered a novel potential biomarker of ACM, specifically useful in ACM vs. IVT differentiation.
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Cencioni C, Atlante S, Savoia M, Martelli F, Farsetti A, Capogrossi MC, Zeiher AM, Gaetano C, Spallotta F. The double life of cardiac mesenchymal cells: Epimetabolic sensors and therapeutic assets for heart regeneration. Pharmacol Ther 2016; 171:43-55. [PMID: 27742569 DOI: 10.1016/j.pharmthera.2016.10.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Organ-specific mesenchymal cells naturally reside in the stroma, where they are exposed to some environmental variables affecting their biology and functions. Risk factors such as diabetes or aging influence their adaptive response. In these cases, permanent epigenetic modifications may be introduced in the cells with important consequences on their local homeostatic activity and therapeutic potential. Numerous results suggest that mesenchymal cells, virtually present in every organ, may contribute to tissue regeneration mostly by paracrine mechanisms. Intriguingly, the heart is emerging as a source of different cells, including pericytes, cardiac progenitors, and cardiac fibroblasts. According to phenotypic, functional, and molecular criteria, these should be classified as mesenchymal cells. Not surprisingly, in recent years, the attention on these cells as therapeutic tools has grown exponentially, although only very preliminary data have been obtained in clinical trials to date. In this review, we summarized the state of the art about the phenotypic features, functions, regenerative properties, and clinical applicability of mesenchymal cells, with a particular focus on those of cardiac origin.
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Affiliation(s)
- Chiara Cencioni
- Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Sandra Atlante
- Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Matteo Savoia
- Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany; Universitá Cattolica, Institute of Medical Pathology, 00138 Rome, Italy; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan 20097, Italy.
| | - Antonella Farsetti
- Consiglio Nazionale delle Ricerche, Istituto di Biologia Cellulare e Neurobiologia, Roma, Italy; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Maurizio C Capogrossi
- Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Roma, Italy.
| | - Andreas M Zeiher
- Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Carlo Gaetano
- Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
| | - Francesco Spallotta
- Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany; Internal Medicine Clinic III, Department of Cardiology, Goethe University, Frankfurt am Main 60596, Germany.
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Feng LB, Pang XM, Zhang L, Li JP, Huang LG, Su SY, Zhou X, Li SH, Xiang HY, Chen CY, Liu JL. MicroRNA involvement in mechanism of endogenous protection induced by fastigial nucleus stimulation based on deep sequencing and bioinformatics. BMC Med Genomics 2015; 8:79. [PMID: 26597292 PMCID: PMC4657244 DOI: 10.1186/s12920-015-0155-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/18/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neurogenic neuroprotection is a promising approach for treating patients with ischemic brain lesions. Fastigial nucleus stimulation (FNS) has been shown to reduce the tissue damage resulting from focal cerebral ischemia in the earlier studies. However, the mechanisms of neuroprotection induced by FNS remain unclear. MicroRNAs (miRNAs) are a newly discovered group of non-coding small RNA molecules that negatively regulate target gene expression and involved in the regulation of pathological process. To date, there is a lack of knowledge on the expression of miRNA in response to FNS. Thus, we study the regulation of miRNAs in the rat ischemic brain by the neuroprotection effect of FNS. METHODS In this study, we used an established focal cerebral ischemia/reperfusion (IR) model in rats. MiRNA expression profile of rat ischemic cortex after 1 h of FNS were investigated using deep sequencing. Microarray was performed to study the expression pattern of miRNAs. Functional annotation on the miRNA was carried out by bioinformatics analysis. RESULTS Two thousand four hundred ninety three miRNAs were detected and found to be miRNAs or miRNA candidates using deep sequencing technology. We found that the FNS-related miRNAs were differentially expressed according microarray data. Bioinformatics analysis indicated that several differentially expressed miRNAs might be a central node of neuroprotection-associated genetic networks and contribute to neuroprotection induced by FNS. CONCLUSIONS MiRNA acts as a novel regulator and contributes to FNS-induced neuroprotection. Our study provides a better understanding of neuroprotection induced by FNS.
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Affiliation(s)
- Ling-Bo Feng
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Xiao-Min Pang
- Department of Neurology, the First People's Hospital of Nanning, Guangxi Medical University, Nanning, China.
| | - Lei Zhang
- Department of Neurology, Dongguan Kanghua hospital, Dongguan, Guangdong, China.
| | - Jin-Pin Li
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Li-Gang Huang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Sheng-You Su
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Xia Zhou
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Sheng-Hua Li
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Hui-Yao Xiang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Chun-Yong Chen
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
| | - Jing-Li Liu
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China.
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Ma X, Wu F, Xin L, Su G, He F, Yang Y, Sun J, Liu Z. Differential plasma microRNAs expression in juvenile idiopathic arthritis. Mod Rheumatol 2015; 26:224-32. [DOI: 10.3109/14397595.2015.1060663] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Xiaolin Ma
- Department of Rheumatism, Capital Institute of Pediatrics, Beijing, China
| | - Fengqi Wu
- Department of Rheumatism, Capital Institute of Pediatrics, Beijing, China
| | - Le Xin
- Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Gaixiu Su
- Department of Rheumatism, Capital Institute of Pediatrics, Beijing, China
| | - Feng He
- Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Yang Yang
- Department of Radiology, Capital Institute of Pediatrics, Beijing, China
| | - Juan Sun
- Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China
| | - Zhewei Liu
- Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China
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11
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Ischemic postconditioning altered microRNAs in human valve replacement. J Surg Res 2015; 200:28-35. [PMID: 26253453 DOI: 10.1016/j.jss.2015.07.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 06/04/2015] [Accepted: 07/03/2015] [Indexed: 01/03/2023]
Abstract
BACKGROUND Although the involvement of microRNAs (miRNAs) has been intensively studied in myocardial infarction, there is no report on the regulation of miRNAs by ischemic postconditioning in patients undergoing cardiac surgery. We aim to explore the regulation of miRNAs by ischemic postconditioning in double valve replacement. MATERIALS AND METHODS In this prospective, controlled clinical study, consecutive 30 patients undergoing double valve replacement were enrolled. The patients were randomized into two groups, namely an ischemic postconditioning (IPO) group (n = 15) and a control (CON) group (n = 15). For ethical considerations, samples of right atrial muscle were harvested, respectively, 10 min before cardiopulmonary bypass (pre-CPB) and 5 min after aortic declamping (post-CPB) for analysis of miRNAs, genes and apoptosis. RESULTS Compared with the CON group, miR-1 was downregulated, whereas miR-21 was upregulated, and BCL2 messenger RNA (mRNA) was upregulated, whereas BAX mRNA and programmed cell death 4 mRNA remained unchanged in the IPO group. Likewise, a significant increase in BCL2 protein and a striking decrease in BAX protein were observed in the IPO group when compared with those in the CON group. The IPO group showed a significantly smaller increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive myocytes after CPB than CON group. CONCLUSIONS Ischemic postconditioning could regulate miR-1, miR-21, and downstream effectors and resulted in actual attenuation of apoptosis in patients undergoing valvular heart surgery.
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12
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The mesmiRizing complexity of microRNAs for striated muscle tissue engineering. Adv Drug Deliv Rev 2015; 88:37-52. [PMID: 25912658 DOI: 10.1016/j.addr.2015.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 03/31/2015] [Accepted: 04/15/2015] [Indexed: 12/12/2022]
Abstract
microRNAs (miRs) are small non-protein-coding RNAs, able to post-transcriptionally regulate many genes and exert pleiotropic effects. Alteration of miR levels in tissues and in the circulation has been associated with various pathological and regenerative conditions. In this regard, tissue engineering of cardiac and skeletal muscles is a fascinating context for harnessing the complexity of miR-based circuitries and signals. In this review, we will focus on miR-driven regulation of cardiac and skeletal myogenic routes in homeostatic and challenging states. Furthermore, we will survey the intriguing perspective of exosomal and circulating miRs as novel paracrine players, potentially useful for current and future approaches of regenerative medicine for the striated muscles.
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Lin Y, Sibanda VL, Zhang HM, Hu H, Liu H, Guo AY. MiRNA and TF co-regulatory network analysis for the pathology and recurrence of myocardial infarction. Sci Rep 2015; 5:9653. [PMID: 25867756 PMCID: PMC4394890 DOI: 10.1038/srep09653] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 03/16/2015] [Indexed: 12/15/2022] Open
Abstract
Myocardial infarction (MI) is a leading cause of death in the world and many genes are involved in it. Transcription factor (TFs) and microRNAs (miRNAs) are key regulators of gene expression. We hypothesized that miRNAs and TFs might play combinatory regulatory roles in MI. After collecting MI candidate genes and miRNAs from various resources, we constructed a comprehensive MI-specific miRNA-TF co-regulatory network by integrating predicted and experimentally validated TF and miRNA targets. We found some hub nodes (e.g. miR-16 and miR-26) in this network are important regulators, and the network can be severed as a bridge to interpret the associations of previous results, which is shown by the case of miR-29 in this study. We also constructed a regulatory network for MI recurrence and found several important genes (e.g. DAB2, BMP6, miR-320 and miR-103), the abnormal expressions of which may be potential regulatory mechanisms and markers of MI recurrence. At last we proposed a cellular model to discuss major TF and miRNA regulators with signaling pathways in MI. This study provides more details on gene expression regulation and regulators involved in MI progression and recurrence. It also linked up and interpreted many previous results.
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Affiliation(s)
- Ying Lin
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Vusumuzi Leroy Sibanda
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Hong-Mei Zhang
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Hui Hu
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Hui Liu
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - An-Yuan Guo
- Hubei Bioinformatics &Molecular Imaging Key Laboratory, Department of Biomedical Engineering, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
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14
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Devaux Y, Mueller M, Haaf P, Goretti E, Twerenbold R, Zangrando J, Vausort M, Reichlin T, Wildi K, Moehring B, Wagner DR, Mueller C. Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain. J Intern Med 2015; 277:260-271. [PMID: 24345063 DOI: 10.1111/joim.12183] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVES To address the diagnostic value of circulating microRNAs (miRNAs) in patients presenting with acute chest pain. DESIGN In a prospective, international, multicentre study, six miRNAs (miR-133a, miR-208b, miR-223, miR-320a, miR-451 and miR-499) were simultaneously measured in a blinded fashion in 1155 unselected patients presenting with acute chest pain to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. The clinical follow-up period was 2 years. RESULTS Acute myocardial infarction (AMI) was the adjudicated final diagnosis in 224 patients (19%). Levels of miR-208b, miR-499 and miR-320a were significantly higher in patients with AMI compared to those with other final diagnoses. MiR-208b provided the highest diagnostic accuracy for AMI (area under the receiver operating characteristic curve 0.76, 95% confidence interval 0.72-0.80). This diagnostic value was lower than that of the fourth-generation cardiac troponin T (cTnT; 0.84) or the high-sensitivity cTnT (hs-cTnT; 0.94; both P < 0.001 for comparison). None of the six miRNAs provided added diagnostic value when combined with cTnT or hs-cTnT (ns for the comparison of combinations vs. cTnT or hs-cTnT alone). During follow-up, 102 (9%) patients died. Levels of MiR-208b were higher in patients who died within 30 days, but the prognostic accuracy was low to moderate. None of the miRNAs predicted long-term mortality. CONCLUSION The miRNAs investigated in this study do not seem to provide incremental diagnostic or prognostic value in patients presenting with suspected AMI.
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Affiliation(s)
- Y Devaux
- Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg
| | - M Mueller
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - P Haaf
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - E Goretti
- Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg
| | - R Twerenbold
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - J Zangrando
- Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg
| | - M Vausort
- Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg
| | - T Reichlin
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - K Wildi
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - B Moehring
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
| | - D R Wagner
- Laboratory of Cardiovascular Research, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg.,Department of Cardiology, Centre Hospitalier, Luxembourg, Luxembourg, for The GREAT network
| | - C Mueller
- Department of Cardiology, University Hospital Basel, Basel, Switzerland
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Sun L, Sun S, Zeng S, Li Y, Pan W, Zhang Z. Expression of circulating microRNA-1 and microRNA-133 in pediatric patients with tachycardia. Mol Med Rep 2015; 11:4039-46. [PMID: 25625292 PMCID: PMC4394928 DOI: 10.3892/mmr.2015.3246] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 05/22/2014] [Indexed: 11/27/2022] Open
Abstract
Paroxysmal or persistent tachycardia in pediatric patients is a common disease. Certain circulating microRNAs (miRNAs) have been associated with arrhythmia. The present study investigated miRNAs in the plasma of pediatric patients with tachycardia. Forty pediatric subjects were included retrospectively: 24 with recurrent sustained tachycardia [seven cases of ventricular tachycardia (VT) and 17 cases of supraventricular tachycardia (SVT)] and 16 healthy controls. Circulating miR-1 and miR-133 in the plasma were detected by fluorescent quantitative polymerase chain reaction. miR-1 levels were significantly decreased in the arrhythmia group compared with those in the controls (P=0.004) whilst miR-133 expression levels were not significantly different between the two groups (P=0.456). Both miR-1 and miR-133 levels showed significant differences between the SVT and VT groups (P=0.004 and P=0.046, respectively), and a significant decrease in miR-1 levels was observed in the SVT group as compared with the controls (P<0.001). No significant difference was observed in the expression levels of miR-133. By contrast, miR-133 levels were significantly increased in the VT group compared with those in the controls (P=0.024), whereas no statistically significant difference was observed in the expression levels of miR-1. Receiver operating characteristic curves showed that 1/miR-1 was significant for the evaluation of tachycardia. Additionally, miR-1 produced enhanced sensitivity and specificity for the evaluation of SVT compared with miR-133, whereas miR-133 was a better marker to assess VT. This study demonstrated that miRNAs may be appropriate markers for pediatric tachycardia; miR-1 levels were decreased in the arrhythmia group compared with those in the healthy controls. Furthermore, patients with SVT had lower miR-1 expression levels while those with VT had higher miR-133 expression levels.
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Affiliation(s)
- Ling Sun
- Department of Pediatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Shuo Sun
- Department of Cardiology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Shaoying Zeng
- Department of Pediatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Yufen Li
- Department of Pediatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Wei Pan
- Department of Pediatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
| | - Zhiwei Zhang
- Department of Pediatrics, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China
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16
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Boštjančič E, Glavač D. miRNome in myocardial infarction: Future directions and perspective. World J Cardiol 2014; 6:939-958. [PMID: 25276296 PMCID: PMC4176804 DOI: 10.4330/wjc.v6.i9.939] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 03/28/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs), which are small and non-coding RNAs, are genome encoded from viruses to humans. They contribute to various developmental, physiological and pathological processes in living organisms. A huge amount of research results revealed that miRNAs regulate these processes also in the heart. miRNAs may have cell-type-specific or tissue-specific expression patterns or may be expressed ubiquitously. Primary studies of miRNA involvement in hypertrophy, heart failure and myocardial infarction analyzed miRNAs that are enriched in or specific for cardiomyocytes; however, growing evidence suggest that other miRNAs, not cardiac or muscle-specific, play a significant role in cardiovascular disease. Abnormal miRNA regulation has been shown to be involved in cardiac diseases, suggesting that miRNAs might affect cardiac structure and function. In this review, we focus on miRNAs that have been found to contribute to the pathogenesis of myocardial infarction (MI) and the response post-MI and characterized as diagnostic, prognostic and therapeutic targets. The majority of these studies were performed using mouse and rat models of MI, with a focus on the identification of basic cellular and molecular pathways involved in MI and in the response post-MI. Much research has also been performed on animal and human plasma samples from MI individuals to identify miRNAs that are possible prognostic and/or diagnostic targets of MI and other MI-related diseases. A large proportion of research is focused on miRNAs as promising therapeutic targets and biomarkers of drug responses and/or stem cell treatment approaches. However, only a few studies have described miRNA expression in human heart tissue following MI.
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Yao Y, Du J, Cao X, Wang Y, Huang Y, Hu S, Zheng Z. Plasma levels of microRNA-499 provide an early indication of perioperative myocardial infarction in coronary artery bypass graft patients. PLoS One 2014; 9:e104618. [PMID: 25111390 PMCID: PMC4128681 DOI: 10.1371/journal.pone.0104618] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 07/10/2014] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Recent studies indicated that microRNAs (miRNAs, miRs) were important for many biological and pathological processes, and they might be potential biomarkers for cardiovascular diseases. The present study aims to determine the release patterns of miRNAs in cardiac surgery and to analyze the ability of miRs to provide early prediction of perioperative myocardial infarction (PMI) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODOLOGY/PRINCIPAL FINDINGS Thirty on-pump CABG patients were recruited in this study; and miR-499, miR-133a and miR-133b, cardiac troponin I (cTnI) were selected for measurement. Serial plasma samples were collected at seven perioperative time points (preoperatively, and 1, 3, 6, 12, 24, and 48 hours after declamping) and were tested for cTnI and miRs levels. Importantly, miR levels peaked as early as 1-3 hours, whereas cTnI levels peaked at 6 hours after declamping. Peak plasma concentrations of miRs correlated significantly with cTnI (miR-499, r = 0.583, P = 0.001; miR-133a, r = 0.514, P = 0.006; miR-133b, r = 0.437, P = 0.05), indicating the degree of myocardial damage. In addition, 30 off-pump CABG patients were recruited; miR-499 and miR-133a levels were tested, which were significantly lower in off-pump group than in on-pump group. A prospective cohort of CABG patients (n = 120) was recruited to study the predictive power of miRs for PMI. The diagnosis of PMI strictly adhered to the principles of universal definition of myocardial infarction. The data analysis revealed that miR-499 had higher sensitivity and specificity than cTnI, and indicated that miR-499 could be an independent risk factor for PMI. CONCLUSION Our results demonstrate that circulating miR-499 is a novel, early biomarker for identifying perioperative myocardial infarction in cardiac surgery.
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Affiliation(s)
- Youxiu Yao
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
- Key Laboratory of Cardiac Regenerative Medicine, Ministry of Health, National Center for Cardiovascular Diseases, Peking, China
| | - Juan Du
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
- Key Laboratory of Cardiac Regenerative Medicine, Ministry of Health, National Center for Cardiovascular Diseases, Peking, China
| | - Xiaoqing Cao
- Department of Thoracic Surgery, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Tongzhou, Beijing, China
| | - Yang Wang
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
| | - Yaohua Huang
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
| | - Shengshou Hu
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
- Key Laboratory of Cardiac Regenerative Medicine, Ministry of Health, National Center for Cardiovascular Diseases, Peking, China
- * E-mail: (ZZ); (SH)
| | - Zhe Zheng
- Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Peking, China
- Department of Cardiac Surgery, Fuwai Hospital and Cardiovascular Institute, Peking, China
- Key Laboratory of Cardiac Regenerative Medicine, Ministry of Health, National Center for Cardiovascular Diseases, Peking, China
- * E-mail: (ZZ); (SH)
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Abstract
The last years have witnessed tremendous technical advances in the field of transcriptomics that enable the simultaneous assessment of nearly all transcripts expressed in a tissue at a given time. These advances harbor the potential to gain a better understanding of the complex biological systems and for the identification and development of novel biomarkers. This article will review the current knowledge of transcriptomics biomarkers in the cardiovascular field and will provide an overview about the promises and challenges of the transcriptomics approach for biomarker identification.
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Affiliation(s)
- Marten Antoon Siemelink
- />Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaanes 100 Room G02.523, PO Box 85500, 3508 GA Utrecht, The Netherlands
| | - Tanja Zeller
- />Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistr. 52, 20246 Hamburg, Germany
- />German Center for Cardiovascular Research (DZHK), Hamburg/Lübeck/Kiel Partner Site, Hamburg, Germany
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19
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Abstract
PURPOSE OF REVIEW Noncoding RNAs (ncRNAs) have gained the attention of molecular biologists and clinicians alike because of the increasing evidence implicating their role in many biological processes and in the development of diseases. In addition to small microRNAs (miRNAs) that play major roles in the post-transcriptional regulation of gene expression, more recently long ncRNAs (lncRNAs, >200 nucleotides) are recognized as being intimately involved in the key cellular processes including transcription and mRNA expression, and having functions in cellular development, differentiation, and development of disease. LncRNAs represent a diverse class of RNAs with many known and likely yet to be discovered functions. This review aims to summarize the emerging roles of lncRNAs in vascular development and disease. RECENT FINDINGS LncRNAs have been recently described to play a role in vascular development, lineage commitment, and in mesoderm differentiation into heart. Additionally, lncRNAs have been associated with angiotensin II actions and with vascular diseases, including coronary heart disease and atherosclerosis. miRNAs, well studied in various vascular diseases, have also been recently shown to be differentially expressed in the biofluids of patients with vascular disease and mediate cell-cell communication. SUMMARY LncRNAs may mediate many different pathways in growth factor actions, vascular development and disease, and are worthy of further investigation because of their potential to serve as novel therapeutic targets.
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Affiliation(s)
- Amy Leung
- Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, California, USA
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20
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Moldovan L, Batte KE, Trgovcich J, Wisler J, Marsh CB, Piper M. Methodological challenges in utilizing miRNAs as circulating biomarkers. J Cell Mol Med 2014; 18:371-90. [PMID: 24533657 PMCID: PMC3943687 DOI: 10.1111/jcmm.12236] [Citation(s) in RCA: 317] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 12/18/2013] [Indexed: 01/06/2023] Open
Abstract
MicroRNAs (miRNAs) have emerged as important regulators in the post-transcriptional control of gene expression. The discovery of their presence not only in tissues but also in extratissular fluids, including blood, urine and cerebro-spinal fluid, together with their changes in expression in various pathological conditions, has implicated these extracellular miRNAs as informative biomarkers of disease. However, exploiting miRNAs in this capacity requires methodological rigour. Here, we report several key procedural aspects of miRNA isolation from plasma and serum, as exemplified by research in cardiovascular and pulmonary diseases. We also highlight the advantages and disadvantages of various profiling methods to determine the expression levels of plasma- and serum-derived miRNAs. Attention to such methodological details is critical, as circulating miRNAs become diagnostic tools for various human diseases.
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Affiliation(s)
- Leni Moldovan
- Division of Pulmonary, Allergy, Critical Care, Sleep Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
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21
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Diagnostic potential of plasmatic MicroRNA signatures in stable and unstable angina. PLoS One 2013; 8:e80345. [PMID: 24260372 PMCID: PMC3829878 DOI: 10.1371/journal.pone.0080345] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 10/01/2013] [Indexed: 01/01/2023] Open
Abstract
Purpose We examined circulating miRNA expression profiles in plasma of patients with coronary artery disease (CAD) vs. matched controls, with the aim of identifying novel discriminating biomarkers of Stable (SA) and Unstable (UA) angina. Methods An exploratory analysis of plasmatic expression profile of 367 miRNAs was conducted in a group of SA and UA patients and control donors, using TaqMan microRNA Arrays. Screening confirmation and expression analysis were performed by qRT-PCR: all miRNAs found dysregulated were examined in the plasma of troponin-negative UA (n=19) and SA (n=34) patients and control subjects (n=20), matched for sex, age, and cardiovascular risk factors. In addition, the expression of 14 known CAD-associated miRNAs was also investigated. Results Out of 178 miRNAs consistently detected in plasma samples, 3 showed positive modulation by CAD when compared to controls: miR-337-5p, miR-433, and miR-485-3p. Further, miR-1, -122, -126, -133a, -133b, and miR-199a were positively modulated in both UA and SA patients, while miR-337-5p and miR-145 showed a positive modulation only in SA or UA patients, respectively. ROC curve analyses showed a good diagnostic potential (AUC ≥ 0.85) for miR-1, -126, and -483-5p in SA and for miR-1, -126, and -133a in UA patients vs. controls, respectively. No discriminating AUC values were observed comparing SA vs. UA patients. Hierarchical cluster analysis showed that the combination of miR-1, -133a, and -126 in UA and of miR-1, -126, and -485-3p in SA correctly classified patients vs. controls with an efficiency ≥ 87%. No combination of miRNAs was able to reliably discriminate patients with UA from patients with SA. Conclusions This work showed that specific plasmatic miRNA signatures have the potential to accurately discriminate patients with angiographically documented CAD from matched controls. We failed to identify a plasmatic miRNA expression pattern capable to differentiate SA from UA patients.
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Abstract
MicroRNAs have been found to play a profound role in embryonic and post-natal development through their regulation of processes such as cell proliferation, differentiation, and morphogenesis. The microRNA-30 (miR-30) family is necessary for vertebrate hepatobiliary development; however, the mechanism through which miR-30 regulates these processes is not fully understood. Here, we identify genes directly regulated by miR-30 that have been characterized as key developmental factors. The targets were confirmed via a luciferase reporter assay, following exogenous over-expression of miR-30a and miR-30c2 in cultured cells. Five novel miR-30ac2 targets were identified using this approach, all of which play crucial roles in hepatobiliary development or are involved in hepatocellular carcinoma and cholangiocarcinoma.
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Affiliation(s)
- Claire L Le Guen
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joshua R Friedman
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J Hand
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Recchioni R, Marcheselli F, Olivieri F, Ricci S, Procopio AD, Antonicelli R. Conventional and novel diagnostic biomarkers of acute myocardial infarction: a promising role for circulating microRNAs. Biomarkers 2013; 18:547-58. [PMID: 24025051 DOI: 10.3109/1354750x.2013.833294] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Biomarkers play a critical role in the diagnosis of acute myocardial infarction (AMI), especially in patients with atypical clinical and/or electrocardiographic presentation or co-morbidities, like the elderly. High-sensitivity assays based on specific biomarkers (e.g. cardiac troponins) enabling earlier AMI diagnosis have recently become available in clinical practice. Although no single biomarker of myocardial necrosis is ever likely to afford AMI diagnosis, a combination including different biomarkers for necrosis and ischemia, like new circulating molecules (microRNAs), could enhance diagnostic specificity. We review the recent literature on conventional and novel AMI biomarkers, with special emphasis on circulating microRNAs.
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Affiliation(s)
- Rina Recchioni
- Center of Clinical Pathology and Innovative Therapy, Italian National Research Center on Aging (I.N.R.C.A-IRCCS) , Ancona , Italy
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Qin H, Chen GX, Liang MY, Rong J, Yao JP, Liu H, Wu ZK. The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury. J Transl Med 2013; 11:154. [PMID: 23800236 PMCID: PMC3694448 DOI: 10.1186/1479-5876-11-154] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 06/14/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND MicroRNAs were enrolled in various cardiovascular disease especially ischemic heart diseases, but the microRNA changes during myocardial ischemia reperfusion injury underwent cardiopulmonary bypass are still unknown. This study screens the microRNA differences in CPB canines and evaluates the relationship of microRNAs with myocardial ischemia reperfusion injury. METHODS 13 healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Left ventricular myocardial samples, blood samples and hemodynamic data were taken at different time points. We performed microRNAs microarray experiments upon the left ventricle myocardium tissue of canines before CPB and after reperfusion for 90 minutes by pooling 3 tissue samples together and used qRT-PCR for confirmation. RESULTS Statistically significant difference was found in mir-499 level before CPB and after reperfusion (T1 vs. T4, p=0.041). We further examined the mir-499 levels by using qRT-PCR in all 13 canines at 4 different time points (T1 vs. T4, p=0.029). Mir-499 expression was negatively correlated with cardiac troponin T (cTnT) and creatine kinase- MB (CK-MB) levels of canines in all time points samples (r=0.469, p<0.001 and r=0.273, p=0.050 respectively). Moreover, higher mir-499 expression level was associated with higher dP/dtmax at 25 minutes and 90 minutes after reperfusion. CONCLUSION Myocardial ischemic reperfusion injury with cardiopulmonary bypass results in declining level of mir-499 expression in left ventricle myocardium of canines, suggesting mir-499 would be a potential therapeutic target in cardiac protection during open heart surgery.
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25
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McGahon MK, Yarham JM, Daly A, Guduric-Fuchs J, Ferguson LJ, Simpson DA, Collins A. Distinctive profile of IsomiR expression and novel microRNAs in rat heart left ventricle. PLoS One 2013; 8:e65809. [PMID: 23799049 PMCID: PMC3683050 DOI: 10.1371/journal.pone.0065809] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 05/03/2013] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs) are single-stranded non-coding RNAs that negatively regulate target gene expression through mRNA cleavage or translational repression. There is mounting evidence that they play critical roles in heart disease. The expression of known miRNAs in the heart has been studied at length by microarray and quantitative PCR but it is becoming evident that microRNA isoforms (isomiRs) are potentially physiologically important. It is well known that left ventricular (patho)physiology is influenced by transmural heterogeneity of cardiomyocyte phenotype, and this likely reflects underlying heterogeneity of gene expression. Given the significant role of miRNAs in regulating gene expression, knowledge of how the miRNA profile varies across the ventricular wall will be crucial to better understand the mechanisms governing transmural physiological heterogeneity. To determinine miRNA/isomiR expression profiles in the rat heart we investigated tissue from different locations across the left ventricular wall using deep sequencing. We detected significant quantities of 145 known rat miRNAs and 68 potential novel orthologs of known miRNAs, in mature, mature* and isomiR formation. Many isomiRs were detected at a higher frequency than their canonical sequence in miRBase and have different predicted targets. The most common miR-133a isomiR was more effective at targeting a construct containing a sequence from the gelsolin gene than was canonical miR-133a, as determined by dual-fluorescence assay. We identified a novel rat miR-1 homolog from a second miR-1 gene; and a novel rat miRNA similar to miR-676. We also cloned and sequenced the rat miR-486 gene which is not in miRBase (v18). Signalling pathways predicted to be targeted by the most highly detected miRNAs include Ubiquitin-mediated Proteolysis, Mitogen-Activated Protein Kinase, Regulation of Actin Cytoskeleton, Wnt signalling, Calcium Signalling, Gap junctions and Arrhythmogenic Right Ventricular Cardiomyopathy. Most miRNAs are not expressed in a gradient across the ventricular wall, with exceptions including miR-10b, miR-21, miR-99b and miR-486.
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Affiliation(s)
- Mary K. McGahon
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - Janet M. Yarham
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - Aideen Daly
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - Jasenka Guduric-Fuchs
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - Lyndsey J. Ferguson
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - David A. Simpson
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
| | - Anthony Collins
- Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, County Antrim, United Kingdom
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Bengel FM, George RT, Schuleri KH, Lardo AC, Wollert KC. Image-guided therapies for myocardial repair: concepts and practical implementation. Eur Heart J Cardiovasc Imaging 2013; 14:741-51. [PMID: 23720377 DOI: 10.1093/ehjci/jet038] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cell- and molecule-based therapeutic strategies to support wound healing and regeneration after myocardial infarction (MI) are under development. These emerging therapies aim at sustained preservation of ventricular function by enhancing tissue repair after myocardial ischaemia and reperfusion. Such therapies will benefit from guidance with regard to timing, regional targeting, suitable candidate selection, and effectiveness monitoring. Such guidance is effectively obtained by non-invasive tomographic imaging. Infarct size, tissue characteristics, muscle mass, and chamber geometry can be determined by magnetic resonance imaging and computed tomography. Radionuclide imaging can be used for the tracking of therapeutic agents and for the interrogation of molecular mechanisms such as inflammation, angiogenesis, and extracellular matrix activation. This review article portrays the hypothesis that an integrated approach with an early implementation of structural and molecular tomographic imaging in the development of novel therapies will provide a framework for achieving the goal of improved tissue repair after MI.
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Affiliation(s)
- Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
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Bao Y, Lin C, Ren J, Liu J. MicroRNA-384-5p regulates ischemia-induced cardioprotection by targeting phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta (PI3K p110δ). Apoptosis 2013; 18:260-70. [DOI: 10.1007/s10495-013-0802-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Olivieri F, Antonicelli R, Capogrossi MC, Procopio AD. Circulating microRNAs (miRs) for diagnosing acute myocardial infarction: an exciting challenge. Int J Cardiol 2012. [PMID: 23194784 DOI: 10.1016/j.ijcard.2012.11.103] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Song JT, Hu B, Qu HY, Bi CL, Huang XZ, Zhang M. Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells. PLoS One 2012; 7:e47657. [PMID: 23082189 PMCID: PMC3474731 DOI: 10.1371/journal.pone.0047657] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 09/14/2012] [Indexed: 12/31/2022] Open
Abstract
Objectives Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs). Methods and Results RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. Conclusions Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.
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Affiliation(s)
- Jian tao Song
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China
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Allegra A, Alonci A, Campo S, Penna G, Petrungaro A, Gerace D, Musolino C. Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review). Int J Oncol 2012; 41:1897-912. [PMID: 23026890 DOI: 10.3892/ijo.2012.1647] [Citation(s) in RCA: 266] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 08/16/2012] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding, endogenous, single-stranded RNAs. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and cancer. However, while the majority of miRNAs are found intracellularly, a significant number of miRNAs have been observed outside of cells, including various body fluids. Circulating miRNAs function as 'extracellular communication RNAs' that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformation. The interest in circulating miRNAs reflects in fact their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, immune-related diseases as well as others. In our review we aimed to summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Additionally, the role of circulating miRNAs could be particularly relevant in the context of neoplastic diseases. At least 79 miRNAs have been reported as plasma or serum miRNA biomarkers of solid and hematologic tumors. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients.
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