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Luo F, Liu W, Bu H. MicroRNAs in hypertrophic cardiomyopathy: pathogenesis, diagnosis, treatment potential and roles as clinical biomarkers. Heart Fail Rev 2022; 27:2211-2221. [PMID: 35332416 DOI: 10.1007/s10741-022-10231-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2022] [Indexed: 12/28/2022]
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and is characterized by increased left ventricular wall thickness, but existing diagnostic and treatment approaches face limitations. MicroRNAs (miRNAs) are type of noncoding RNA molecule that plays crucial roles in the pathological process of cardiac remodelling. Accordingly, miRNAs related to HCM may represent potential novel therapeutic targets. In this review, we first discuss the different roles of miRNAs in the development of HCM. We then summarize the roles of common miRNAs as diagnostic and clinical biomarkers in HCM. Finally, we outline current and future challenges and potential new directions for miRNA-based therapeutics for HCM.
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Affiliation(s)
- Fanyan Luo
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Liu
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Haisong Bu
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China. .,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Scolari FL, Faganello LS, Garbin HI, Piva E Mattos B, Biolo A. A systematic review of microRNAs in patients with hypertrophic cardiomyopathy. Int J Cardiol 2020; 327:146-154. [PMID: 33212095 DOI: 10.1016/j.ijcard.2020.11.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/20/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Several microRNAs (miRNA) have been associated with hypertrophic cardiomyopathy (HCM), but studies differ regarding methods employed. In an attempt to understand their role in the disease, we performed a systematic review of studies assessing miRNAs and their association with HCM. METHODS The literature search was based on The Medical Subject Headings (MeSH) terms "Hypertrophic Cardiomyopathy" and "MicroRNA" combined with other synonyms on Embase, Medline and LILACS databases in April 2020. The selected studies and data extraction were independently evaluated. Only human reports with a clear definition of HCM diagnosis were included. RESULTS The search found 68 studies, 13 fulfilled the selection criteria, with a total of 329 patients. Eighty-seven miRNA were differentially expressed in HCM patients, being mir-21, mir-29a and mir-133 the most reported. The miRNA were mainly up-regulated, where mir-29a was up-regulated in 6 studies, followed by mir-133 in 4 and mir-21 in 3. The other miRNAs were mainly up-regulated. Blood samples were evaluated in the majority of patients (86%), but a greater number of miRNAs (79%) were assessed in myocardium. Six studies evaluating the phenotype correlation demonstrated that several miRNAs, mainly mir-1-3p, mir-19b, mir-21, mir-29a, mir-155, and mir-221, were related to either hypertrophy or fibrosis. Mir-29a showed a more consistent phenotypic correlation. CONCLUSION Eighty-seven miRNAs were differentially expressed in HCM patients, the majority in up-regulation. Mir-21, mir-29a and mir-133 were the most reported. Correlation with left ventricular hypertrophy and fibrosis was evaluated in six studies for several miRNAs, nevertheless, mir-29a showed more consistent findings and seems to be a promising biomarker.
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Affiliation(s)
- Fernando Luís Scolari
- Division of Cardiology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Faculty of Medicine, Universidade Federal do Rio Grande do Sul, 2350 Ramiro Barcelos St, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Lucas Simonetto Faganello
- Department of Cardiac Electrophysiology, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec H4A 3J1, Canada
| | - Henrique Iahnke Garbin
- Faculty of Medicine, Universidade Federal do Rio Grande do Sul, 2350 Ramiro Barcelos St, Porto Alegre, Rio Grande do Sul, Brazil
| | - Beatriz Piva E Mattos
- Division of Cardiology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Faculty of Medicine, Universidade Federal do Rio Grande do Sul, 2350 Ramiro Barcelos St, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Andreia Biolo
- Division of Cardiology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Faculty of Medicine, Universidade Federal do Rio Grande do Sul, 2350 Ramiro Barcelos St, Porto Alegre, Rio Grande do Sul, Brazil.
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Di Stefano AB, Pappalardo M, Moschella F, Cordova A, Toia F. MicroRNAs in solid organ and vascularized composite allotransplantation: Potential biomarkers for diagnosis and therapeutic use. Transplant Rev (Orlando) 2020; 34:100566. [PMID: 32682704 DOI: 10.1016/j.trre.2020.100566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 12/24/2022]
Abstract
Nowadays, solid organ transplantation (SOT) is an established treatment for patients with end-organ dysfunction, which dramatically improves the quality-of-life. Vascularized composite allotransplants (VCAs) including hand and face have been reported worldwide over the last 20 years. However, VCAs, differently to SOT, are life-enhancing instead of life-saving and are not routinely performed due to the risk of immune rejection and the adverse effects of immunosuppression. Over the past decade, although considerable improvements in short-term outcomes after allotransplantation have been registered, these results have not been translated into major progress in long-term allograft acceptance and patient survival. Recently active researches in the field of biomarker discovery have been conducted to develop individualized therapies for allograft recipients. MicroRNAs (miRNAs) are a small noncoding RNAs functioning as critical regulators of gene and protein expression by RNA interference. They have been connected in numerous biological processes and diseases. Due to their immunomodulatory functions, miRNAs have been amended as potential diagnostic and prognostic biomarker for the detection of rejection in allotransplantation. Due to their specific circulating expression profile, they could act as noninvasive predictive tools for rejection that may help clinicians in an early adjustment of the immunosuppression protocol during acute rejections episodes. Indeed, specific anti-sense oligonucleotides suppressing miRNAs expressed in rejection could reduce the rejection rate in allografts and decrease the use of immunosuppressants. We present a literature review of the immunomodulatory properties and characteristics of miRNAs. We will summarize the current knowledge on miRNAs as potential biomarkers for allograft rejection and possible application in allotransplantation monitoring. Finally, we will discuss the advances in preclinical miRNA-based therapies for immunosuppression.
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Affiliation(s)
- Anna Barbara Di Stefano
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Marco Pappalardo
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Francesco Moschella
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Adriana Cordova
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
| | - Francesca Toia
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
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Soler-Botija C, Gálvez-Montón C, Bayés-Genís A. Epigenetic Biomarkers in Cardiovascular Diseases. Front Genet 2019; 10:950. [PMID: 31649728 PMCID: PMC6795132 DOI: 10.3389/fgene.2019.00950] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 09/05/2019] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular diseases are the number one cause of death worldwide and greatly impact quality of life and medical costs. Enormous effort has been made in research to obtain new tools for efficient and quick diagnosis and predicting the prognosis of these diseases. Discoveries of epigenetic mechanisms have related several pathologies, including cardiovascular diseases, to epigenetic dysregulation. This has implications on disease progression and is the basis for new preventive strategies. Advances in methodology and big data analysis have identified novel mechanisms and targets involved in numerous diseases, allowing more individualized epigenetic maps for personalized diagnosis and treatment. This paves the way for what is called pharmacoepigenetics, which predicts the drug response and develops a tailored therapy based on differences in the epigenetic basis of each patient. Similarly, epigenetic biomarkers have emerged as a promising instrument for the consistent diagnosis and prognosis of cardiovascular diseases. Their good accessibility and feasible methods of detection make them suitable for use in clinical practice. However, multicenter studies with a large sample population are required to determine with certainty which epigenetic biomarkers are reliable for clinical routine. Therefore, this review focuses on current discoveries regarding epigenetic biomarkers and its controversy aiming to improve the diagnosis, prognosis, and therapy in cardiovascular patients.
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Affiliation(s)
- Carolina Soler-Botija
- Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Gálvez-Montón
- Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Antoni Bayés-Genís
- Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
- Cardiology Service, HUGTiP, Badalona, Spain
- Department of Medicine, Barcelona Autonomous University (UAB), Badalona, Spain
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5
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Liu H, Chen B, Zhu Q. RETRACTED ARTICLE: Long non-coding RNA SNHG16 reduces hydrogen peroxide-induced cell injury in PC-12 cells by up-regulating microRNA-423-5p. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1444-1451. [PMID: 30977409 DOI: 10.1080/21691401.2019.1600530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Haochuan Liu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bing Chen
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qingsan Zhu
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
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6
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Yang S, Li H, Chen L. MicroRNA-140 attenuates myocardial ischemia-reperfusion injury through suppressing mitochondria-mediated apoptosis by targeting YES1. J Cell Biochem 2018; 120:3813-3821. [PMID: 30259997 DOI: 10.1002/jcb.27663] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/21/2018] [Indexed: 12/21/2022]
Abstract
Myocardial ischemia-reperfusion (I/R) injury is thought to have its detrimental role in coronary heart disease (CHD), which is considered as the foremost cause of death all over the world. However, molecular mechanism in the progression of myocardial I/R injury is still unclear. The goal of this study was to investigate the expression and function of microRNA-140 (miR-140) in the process of myocardial I/R injury. The miR-140 expression level was analyzed in the myocardium with I/R injury and control myocardium using quantitative real-time polymerase chain reaction. Then the relation between the level of miR-140 and YES proto-oncogene 1 (YES1) was also investigated via luciferase reporter assay. Assessment of myocardial infarct size measurement of serum myocardial enzymes and electron microscopy analysis were used for analyzing the effect of miR-140 on myocardial I/R injury. We also used Western blot analysis to examine the expression levels of the mitochondrial fission-related proteins, Drp1 and Fis1. miR-140 is downregulated, and YES1 is upregulated after myocardial I/R injury. Overexpression of miR-140 could reduce the increase related to myocardial I/R injury in infarct size and myocardial enzymes, and it also could inhibit the expression of proteins related to mitochondrial morphology and myocardial I/R-induced mitochondrial apoptosis by targeting YES1. Taken together, these findings may provide a novel insight into the molecular mechanism of miR-140 and YES1 in the progression of myocardial I/R injury. MiR-140 might become a promising therapeutic target for treating myocardial I/R injury.
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Affiliation(s)
- Shuguo Yang
- Department of Cardiology, Linyi Central Hospital, Linyi, Shandong, China
| | - Haide Li
- Department of Cardiology, Linyi Central Hospital, Linyi, Shandong, China
| | - Lianghua Chen
- Department of Cardiology, Shandong Provincial Hospital, Jinan, Shandong, China
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7
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Jia W, Yu T, An Q, Cao X, Pan H. MicroRNA-423-5p inhibits colon cancer growth by promoting caspase-dependent apoptosis. Exp Ther Med 2018; 16:1225-1231. [PMID: 30116373 PMCID: PMC6090304 DOI: 10.3892/etm.2018.6288] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 12/01/2017] [Indexed: 12/12/2022] Open
Abstract
Plasma microRNA (miR)-423-5p is a potential biomarker for the detection of colon cancer. However, the expression and biological role of miR-423-5p in colon tumorigenesis remains unclear. In the current study, reverse transcription-quantitative polymerase chain reaction was used to determine miR-423-5p expression in malignant colon tissues and plasma from patients with colon cancer. Cell viability, colony formation and apoptosis assays, as well as western blotting, were performed to investigate the biological role and regulatory mechanisms of miR-423-5p in colon cancer. The results demonstrated that miR-423-5p expression was downregulated in tumor tissues and plasma from patients with colon cancer, as well as in colon cancer cell lines. Furthermore, overexpression of miR-423-5p promoted colon cancer cell apoptosis and resulted in the inhibition of cell proliferation and colony formation. Mechanistically, miR-423-5p induced the expression of caspases 3, 8 and 9, as well as p53 in colon cancer. The effect of z-VAD treatment indicated that the miR-423-5p-mediated colon cancer cell apoptosis is caspase-dependent. These results suggest that miR-423-5p is a tumor suppressor in colon cancer and a potential diagnostic target to enable the early detection of colon cancer.
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Affiliation(s)
- Wenzhuo Jia
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing 100730, P.R. China
| | - Tao Yu
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing 100730, P.R. China
| | - Qi An
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing 100730, P.R. China
| | - Xianglong Cao
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing 100730, P.R. China
| | - Hongda Pan
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing 100730, P.R. China
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Xu J, He J, Huang H, Peng R, Xi J. MicroRNA-423-3p promotes glioma growth by targeting PANX2. Oncol Lett 2018; 16:179-188. [PMID: 29928399 PMCID: PMC6006452 DOI: 10.3892/ol.2018.8636] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 03/15/2018] [Indexed: 01/08/2023] Open
Abstract
Previously, a number of microRNAs (miRs) have been identified to participate in the development and progression of glioma via the regulation of their target genes. However, the molecular mechanisms underlying the effect of miR-423-3p in glioma growth remain unclear. In the present study, the reverse transcription-quantitative polymerase chain reaction and western blotting were used to assess the mRNA and protein expression levels of miR-423-3p, respectively. An MTT assay and flow cytometry were performed to determine cell proliferation and apoptosis, respectively. A luciferase reporter gene assay was performed to determine the target association between pannexin 2 (PANX2) and miR-423-3p. It was revealed that miR-423-3p was significantly upregulated in glioma tissues compared with normal brain tissues, and the increased expression of miR-423-3p was significantly associated with an advanced grade as well as a poorer prognosis of patients with glioma. Inhibition of miR-423-3p using an miR-423-3p inhibitor resulted in the decreased proliferation of glioma U251 and U87MG Uppsala cells, and the induction of apoptosis. PANX2 was identified as a novel target gene of miR-423-3p, and the expression of PANX2 was revealed to be increased in U251 and U87MG Uppsala cells when miR-423-3p was inhibited. Knockdown of PANX2 attenuated the effects of miR-423-3p inhibition on glioma cell proliferation and apoptosis. Furthermore, PANX2 was significantly downregulated in glioma tissues compared with normal brain tissues, and its levels were markedly lower in World Health Organization (WHO) stage III–IV gliomas compared with WHO stage I–II gliomas. Additionally, the expression levels of PANX2 were identified to be inversely correlated with miR-423-3p expression levels in glioma tissues. Consequently, targeting miR-423-3p may inhibit glioma growth via the upregulation of PANX2.
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Affiliation(s)
- Jing Xu
- Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jian He
- Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - He Huang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Renjun Peng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jian Xi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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De Rosa S, Eposito F, Carella C, Strangio A, Ammirati G, Sabatino J, Abbate FG, Iaconetti C, Liguori V, Pergola V, Polimeni A, Coletta S, Gareri C, Trimarco B, Stabile G, Curcio A, Indolfi C, Rapacciuolo A. Transcoronary concentration gradients of circulating microRNAs in heart failure. Eur J Heart Fail 2018; 20:1000-1010. [PMID: 29314582 DOI: 10.1002/ejhf.1119] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 11/12/2017] [Accepted: 11/16/2017] [Indexed: 01/16/2023] Open
Abstract
AIMS Circulating levels of microRNAs (miRNAs) are emergent promising biomarkers for cardiovascular disease. Altered expression of miRNAs has been related to heart failure (HF) and cardiac remodelling. We measured the concentration gradients across the coronary circulation to assess their usefulness to diagnose HF of different aetiologies. METHODS AND RESULTS Circulating miRNAs were measured in plasma samples simultaneously obtained from the aorta and the coronary venous sinus in patients with non-ischaemic HF (NICM-HF, n = 23) ischaemic HF (ICM-HF, n = 41), and in control patients (n = 11). A differential modulation of circulating levels of miR-423, -34a, -21-3p, -126, -199 and -30a was found across the aetiology groups. Interestingly, a positive transcoronary gradient was found for miR-423 (P < 0.001) and miR-34a (P < 0.001) only in the ICM-HF group. On the contrary, a positive gradient was found for miR-21-3p (P < 0.001) and miR-30a (P = 0.030) only in the NICM-HF group. Finally, no significant variations were observed in the transcoronary gradient of miR-126 or miR-199. CONCLUSIONS The present findings suggest that circulating levels of miRNAs are differentially expressed in patients with HF of different aetiologies. The presence of a transcoronary concentration gradient suggests a selective release of miRNAs by the failing heart into the coronary circulation. The presence of aetiology-specific transcoronary concentration gradients in HF patients might provide important information to better understand their role in HF, and suggests they could be useful biomarkers to distinguish HF of different aetiologies.
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Affiliation(s)
- Salvatore De Rosa
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Francesca Eposito
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Cristina Carella
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Antonio Strangio
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Giuseppe Ammirati
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Jolanda Sabatino
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Fabio Giovanni Abbate
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Claudio Iaconetti
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Vincenzo Liguori
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Valerio Pergola
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Alberto Polimeni
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Silvio Coletta
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | - Clarice Gareri
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Bruno Trimarco
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
| | | | - Antonio Curcio
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Ciro Indolfi
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.,URT-CNR of IFC, Magna Graecia University, Catanzaro, Italy
| | - Antonio Rapacciuolo
- Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
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He X, Ji J, Wang T, Wang MB, Chen XL. Upregulation of Circulating miR-195-3p in Heart Failure. Cardiology 2017; 138:107-114. [PMID: 28618405 DOI: 10.1159/000476029] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 04/25/2017] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Many circulating microRNAs (miRs) have been shown to have potential biomarker effects in cardiovascular disease. We studied the dysregulation of circulating miR-195-3p in patients with heart failure (HF) to elucidate its value as a potential biomarker for HF. METHODS Eight ischemic HF (IHF) patients, 8 nonischemic HF patients (NIHF), and 8 healthy volunteers (matched by age and sex - normal controls [NCs]) were chosen for miR sequencing. The plasma RNA was extracted, and a small RNA library of HF was established and then sequenced using next-generation sequencing (NGS) technology. The miR-195-3p was selected for a second clinical study in 60 IHF, 48 NIHF patients, and 35 NCs for qRT-PCR validation. RESULTS The expression of circulating miR-195-3p in the IHF group was increased 69.5-fold compared with the NC group using NGS technique, and it was the most elevated in all upregulated miRs. MiR-195-3p was ranked in the top 1 of all upregulated miRs in contribution to HF based on a random forest model analysis. The upregulation of circulating miR-195-3p was also validated with the qRT-PCR method, and receiver operating characteristic curve analysis showed that the area under the curve (AUC) was 0.831. CONCLUSIONS The circulating miR-195-3p was upregulated in IHF and NIHF patients and could be a potential biomarker for HF.
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Affiliation(s)
- Xia He
- Department of Pathology, Shenzhen Sun Yat-Sen Cardiovascular Hospital, Shenzhen, China
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Li H, Fan J, Yin Z, Wang F, Chen C, Wang DW. Identification of cardiac-related circulating microRNA profile in human chronic heart failure. Oncotarget 2016; 7:33-45. [PMID: 26683101 PMCID: PMC4807981 DOI: 10.18632/oncotarget.6631] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 11/20/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND During chronic heart failure, levels of circulating miRNAs endued with characteristics of diseased cells could be identified as biomarkers. In this study, we sought to identify cardiac-related circulating miRNAs as biomarkers of failing heart. METHODS Total RNA of plasma and heart samples was extracted from 10 normal controls and 14 patients with chronic heart failure. Microarray was applied for miRNA profiles. Validation and organ/tissue distribution analysis was performed by qRT-PCR. In addition, bioinformatics analysis was performed to understand the critical roles of these cardiac-related circulating miRNAs in heart failure. RESULTS Results showed that levels of more than half of the miRNAs dysregulated in heart failed to show any differences in plasma. Meanwhile, more than 90% of the miRNAs dysregulated in plasma remained stable in heart. Four cardiac fibroblast-derived miRNAs (miR-660-3p, miR-665, miR-1285-3p and miR-4491) were found significantly upregulated in heart and plasma during heart failure. These 4 miRNAs strongly discriminated patients from controls, and 3 of them showed significant correlations with LVEF. CONCLUSIONS This study provides global profiles of miRNAs changes in plasma and failing heart, and using a circulation-tissue miRNA profiling comparison model, we successfully identify 3 cardiac-related circulating miRNAs as potential biomarkers for diagnosis of heart failure.
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Affiliation(s)
- Huaping Li
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
| | - Jiahui Fan
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
| | - Zhongwei Yin
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
| | - Feng Wang
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
| | - Chen Chen
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
| | - Dao Wen Wang
- Departments of Internal Medicine and The Institute of Hypertension Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Rep. of China
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Schulte C, Westermann D, Blankenberg S, Zeller T. Diagnostic and prognostic value of circulating microRNAs in heart failure with preserved and reduced ejection fraction. World J Cardiol 2015; 7:843-860. [PMID: 26730290 PMCID: PMC4691811 DOI: 10.4330/wjc.v7.i12.843] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/28/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023] Open
Abstract
microRNAs (miRNAs) are powerful regulators of posttranscriptional gene expression and play an important role in pathophysiological processes. Circulating miRNAs can be quantified in body liquids and are promising biomarkers in numerous diseases. In cardiovascular disease miRNAs have been proven to be reliable diagnostic biomarkers for different disease entities. In cardiac fibrosis (CF) and heart failure (HF) dysregulated circulating miRNAs have been identified, indicating their promising applicability as diagnostic biomarkers. Some miRNAs were successfully tested in risk stratification of HF implementing their potential use as prognostic biomarkers. In this respect miRNAs might soon be implemented in diagnostic clinical routine. In the young field of miRNA based research advances have been made in identifying miRNAs as potential targets for the treatment of experimental CF and HF. Promising study results suggest their potential future application as therapeutic agents in treatment of cardiovascular disease. This article summarizes the current state of the various aspects of miRNA research in the field of CF and HF with reduced ejection fraction as well as preserved ejection fraction. The review provides an overview of the application of circulating miRNAs as biomarkers in CF and HF and current approaches to therapeutically utilize miRNAs in this field of cardiovascular disease.
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13
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MicroRNAs as master regulators of immune responses in transplant recipients. Curr Opin Organ Transplant 2015; 20:29-36. [DOI: 10.1097/mot.0000000000000148] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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14
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Sala V, Bergerone S, Gatti S, Gallo S, Ponzetto A, Ponzetto C, Crepaldi T. MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine. Cell Mol Life Sci 2014; 71:1439-52. [PMID: 24218009 PMCID: PMC11113160 DOI: 10.1007/s00018-013-1504-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 10/17/2013] [Accepted: 10/18/2013] [Indexed: 01/16/2023]
Abstract
MicroRNAs (miRNAs) are natural, single-stranded, small RNA molecules which subtly control gene expression. Several studies indicate that specific miRNAs can regulate heart function both in development and disease. Despite prevention programs and new therapeutic agents, cardiovascular disease remains the main cause of death in developed countries. The elevated number of heart failure episodes is mostly due to myocardial infarction (MI). An increasing number of studies have been carried out reporting changes in miRNAs gene expression and exploring their role in MI and heart failure. In this review, we furnish a critical analysis of where the frontier of knowledge has arrived in the fields of basic and translational research on miRNAs in cardiac ischemia. We first summarize the basal information on miRNA biology and regulation, especially concentrating on the feedback loops which control cardiac-enriched miRNAs. A focus on the role of miRNAs in the pathogenesis of myocardial ischemia and in the attenuation of injury is presented. Particular attention is given to cardiomyocyte death (apoptosis and necrosis), fibrosis, neovascularization, and heart failure. Then, we address the potential of miR-diagnosis (miRNAs as disease biomarkers) and miR-drugs (miRNAs as therapeutic targets) for cardiac ischemia and heart failure. Finally, we evaluate the use of miRNAs in the emerging field of regenerative medicine.
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Affiliation(s)
- V. Sala
- Department of Oncology, University of Turin, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - S. Bergerone
- Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy
| | - S. Gatti
- Department of Oncology, University of Turin, Turin, Italy
| | - S. Gallo
- Department of Oncology, University of Turin, Turin, Italy
| | - A. Ponzetto
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - C. Ponzetto
- Department of Oncology, University of Turin, Turin, Italy
| | - T. Crepaldi
- Department of Oncology, University of Turin, Turin, Italy
- Institute of Anatomy, Corso Massimo d’Azeglio 52, 10126 Turin, Italy
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15
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Abstract
Heart failure is a leading cause of death in industrialized nations especially in an aging population. The recent improvements in cardiac revascularization therapy reduced death rates because of myocardial infarction but steadily increased the number of individuals developing cardiac remodeling and heart failure in the future. Conceptual novel approaches entering the clinics to treat cardiac remodeling and heart failure remain scarce. MicroRNAs emerged as powerful and dynamic modifiers of cardiovascular diseases. In this review, the current approaches using microRNAs as novel diagnostic and therapeutic strategies for cardiac remodeling and heart failure are highlighted. Other gene regulatory mechanisms presented include long (>200 bp) noncoding RNAs that function as an additional regulatory machinery of the genome controlling both transcriptional and post-transcriptional events also in the cardiovascular system.
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Affiliation(s)
- Regalla Kumarswamy
- Institute of Molecular and Translational Therapeutic Strategies, Hannover, Germany
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16
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17
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MicroRNAs as biomarkers for ischemic heart disease. J Cardiovasc Transl Res 2013; 6:458-70. [PMID: 23716129 DOI: 10.1007/s12265-013-9466-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 04/19/2013] [Indexed: 01/20/2023]
Abstract
MicroRNAs (miRs) are short, noncoding RNAs that function as posttranscriptional inhibitors of mRNA translation to protein. They are essential for normal development and homeostasis. Dysregulated expression patterns both cause and result from disease states. Generally studied as intracellular mediators, miRs can be isolated from body fluids and exhibit remarkable stability to degradation. These features, in combination with their tissue specificity, make miRs attractive candidates as blood-derived biomarkers for coronary artery disease (CAD), the most frequent cause of death worldwide. The use of miRs as biomarkers in both symptomatic and asymptomatic CAD and the influence of conventional cardiovascular risk factors and CAD treatment on their circulating levels are the topics of this review. To conclude, it highlights the remaining hurdles to tackle before this promising application of miRs can enter into routine clinical practice.
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18
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Abstract
Even in the new millennium, arterial hypertension remains a serious condition, with considerable morbidity and mortality worldwide. Crucial in managing the disease is not only lowering arterial blood pressure but also preventing or treating the typical end-organ damage caused by long-lasting and inadequately treated hypertension. In the past decade, it has been shown that microRNAs (miRs) are involved in several hypertension-related pathologies, such as cardiac hypertrophy and fibrosis, hypertensive heart failure, renal fibrosis, kidney failure, and, to a lesser extent, eye disease and hemorrhagic stroke. Whereas others extensively reviewed the role of miRs in atherosclerosis and vascular disease, this review focuses on their role in target organ damage during arterial hypertension. We emphasize the involvement of miRs in pathological end-organ remodeling processes and try to demonstrate some common miR signatures in distinct end organs. Hence, we aimed to provide proof of arterial hypertension being a systemic disease, similar to diabetes mellitus or metabolic syndrome. Furthermore, miRs that act on one particular process in different end organs are interesting therapeutic targets. Some future perspectives in miR research are highlighted with respect to novel therapeutic strategies in the cardiovascular field.
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Affiliation(s)
- Ward A. Heggermont
- From the Center for Molecular and Vascular Research, University of Leuven, Leuven, Belgium (W.A.H.); Cardiovascular Research Institute, University of Maastricht, Maastricht, the Netherlands (S.H.)
| | - Stephane Heymans
- From the Center for Molecular and Vascular Research, University of Leuven, Leuven, Belgium (W.A.H.); Cardiovascular Research Institute, University of Maastricht, Maastricht, the Netherlands (S.H.)
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19
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Circulation Research
Thematic Synopsis. Circ Res 2012. [DOI: 10.1161/circresaha.112.277137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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20
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Pan Z, Guo Y, Qi H, Fan K, Wang S, Zhao H, Fan Y, Xie J, Guo F, Hou Y, Wang N, Huo R, Zhang Y, Liu Y, Du Z. M3 subtype of muscarinic acetylcholine receptor promotes cardioprotection via the suppression of miR-376b-5p. PLoS One 2012; 7:e32571. [PMID: 22396777 PMCID: PMC3292572 DOI: 10.1371/journal.pone.0032571] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 01/27/2012] [Indexed: 12/13/2022] Open
Abstract
The M3 subtype of muscarinic acetylcholine receptors (M3-mAChR) plays a protective role in myocardial ischemia and microRNAs (miRNAs) participate in many cardiac pathophysiological processes, including ischemia-induced cardiac injury. However, the role of miRNAs in M3-mAChR mediated cardioprotection remains unexplored. The present study was designed to identify miRNAs that are involved in cardioprotective effects of M3-mAChR against myocardial ischemia and elucidate the underlying mechanisms. We established rat model of myocardial ischemia and performed miRNA microarray analysis to identify miRNAs involved in the cardioprotection of M3-mAChR. In H9c2 cells, the viability, intracellular free Ca2+ concentration ([Ca2+]i), intracellular reactive oxygen species (ROS), miR-376b-5p expression level, brain derived neurophic factor (BDNF) and nuclear factor kappa-B (NF-κB) levels were measured. Our results demonstrated that M3-mAChR protected myocardial ischemia injury. Microarray analysis and qRT-PCR revealed that miR-376b-5p was significantly up-regulated in ischemic heart tissue and the M3-mAChRs agonist choline reversed its up-regulation. In vitro, miR-376b-5p promoted H2O2-induced H9c2 cell injuries measured by cells viability, [Ca2+]i and ROS. Western blot and luciferase assay identified BDNF as a direct target of miR-376b-5p. M3-mAChR activated NF-κB and thereby inhibited miR-376b-5p expression. Our data show that a novel M3-mAChR/NF-κB/miR-376b-5p/BDNF axis plays an important role in modulating cardioprotection. MiR-376b-5p promotes myocardial ischemia injury possibly by inhibiting BDNF expression and M3-mAChR provides cardioprotection at least partially mediated by the downregulation of miR-376b-5p through NF-κB. These findings provide new insight into the potential mechanism by which M3-mAChR provides cardioprotection against myocardial ischemia injury.
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Affiliation(s)
- Zhenyu Pan
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Yueping Guo
- Department of Anesthesiology of the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Hanping Qi
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Kai Fan
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Shu Wang
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Hua Zhao
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Yuhua Fan
- Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Jing Xie
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Feng Guo
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Yunlong Hou
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Ning Wang
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Rong Huo
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Yong Zhang
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
| | - Yan Liu
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
- * E-mail: (YL); (ZD)
| | - Zhimin Du
- Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, People′s Republic of China
- * E-mail: (YL); (ZD)
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21
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Abstract
MicroRNAs (miRs) regulate protein expression by inhibiting translation of expressed mRNAs. Targeting by one or more miRs of multiple mRNA transcripts encoding proteins with common functions confers nodal control over cardiac development and stress response. Dynamic coregulation of miRs and their mRNA targets has complicated understanding their biology but also provides opportunities for clinical diagnostics and therapeutics. Here, the biology of miRs is reviewed as it relates to the cardiac system, recent findings are described that illuminate miR control of cardiac development and myofiber identity, and the clinical ramifications of miR expression profiling are illustrated.
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22
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Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, Ziemann M, Helbing T, El-Osta A, Jowett JBM, Peter K. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93:633-44. [PMID: 22258631 PMCID: PMC3291092 DOI: 10.1093/cvr/cvs007] [Citation(s) in RCA: 391] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Aims Circulating microRNAs (miRNAs) have attracted major interest as biomarkers for cardiovascular diseases. Since RNases are abundant in circulating blood, there needs to be a mechanism protecting miRNAs from degradation. We hypothesized that microparticles (MP) represent protective transport vehicles for miRNAs and that these are specifically packaged by their maternal cells. Methods and results Conventional plasma preparations, such as the ones used for biomarker detection, are shown to contain substantial numbers of platelet-, leucocyte-, and endothelial cell-derived MP. To analyse the widest spectrum of miRNAs, Next Generation Sequencing was used to assess miRNA profiles of MP and their corresponding stimulated and non-stimulated cells of origin. THP-1 (monocytic origin) and human umbilical vein endothelial cell (HUVEC) MP were used for representing circulating MP at a high purity. miRNA profiles of MP differed significantly from those of stimulated and non-stimulated maternal THP-1 cells and HUVECs, respectively. Quantitative reverse transcription–polymerase chain reaction of miRNAs which have been associated with cardiovascular diseases also demonstrated significant differences in miRNA profiles between platelets and their MP. Notably, the main fraction of miRNA in plasma was localized in MP. Furthermore, miRNA profiles of MP differed significantly between patients with stable and unstable coronary artery disease. Conclusion Circulating MP represent transport vehicles for large numbers of specific miRNAs, which have been associated with cardiovascular diseases. miRNA profiles of MP are significantly different from their maternal cells, indicating an active mechanism of selective ‘packaging’ from cells into MP. These findings describe an interesting mechanism for transferring gene-regulatory function from MP-releasing cells to target cells via MP circulating in blood.
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Affiliation(s)
- Philipp Diehl
- Atherothrombosis and Vascular Biology, BakerIDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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23
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Abstract
Organ transplantation has evolved rapidly and there is now widespread use of donated organs for the treatment of end-stage organ failure. Although the therapeutic options achieving long-term graft survival have improved, acute and chronic rejections are still a major problem. Studies to identify noninvasive biomarkers for rejection and underlying molecular events have increased significantly in the past decade, but a major breakthrough is still missing. The recent discovery of small regulatory RNA molecules (microRNAs) resulted in a new and improved understanding of the mechanisms of gene regulation and also led to the development of the first new microRNA (miRNA)-based therapies. miRNAs are endogenous, single-stranded RNAs consisting of about 19-25 noncoding nucleotides, which have an important role in regulating gene expression. Additionally, circulating miRNAs that might be useful as novel disease biomarkers were detected. Here, we summarise current knowledge about the role of miRNAs in immunology and transplantation medicine and their role as potential biomarkers. We also focus on the molecular mechanisms and therapeutic implications of the use of miRNA-based therapeutic strategies to improve long-term allograft survival.
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24
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Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M. Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc Res 2011; 93:555-62. [PMID: 22028337 PMCID: PMC3291086 DOI: 10.1093/cvr/cvr266] [Citation(s) in RCA: 200] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The recent discovery that microRNAs (miRNAs) are present in the circulation sparked interest in their use as potential biomarkers. In this review, we will summarize the latest findings on circulating miRNAs and cardiovascular disease but also discuss analytical challenges. While research on circulating miRNAs is still in its infancy, high analytical standards in statistics and study design are a prerequisite to obtain robust data and avoid repeating the mistakes of the early genetic association studies. Otherwise, studies tend to get published because of their novelty despite low numbers, poorly matched cases and controls and no multivariate adjustment for conventional risk factors. Research on circulating miRNAs can only progress by bringing more statistical rigour to bear in this field and by evaluating changes of individual miRNAs in the context of the overall miRNA network. Such miRNA signatures may have better diagnostic and prognostic value.
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Affiliation(s)
- Anna Zampetaki
- King's British Heart Foundation Centre, King' s College London, 125 Coldharbour Lane, London SE5 9NU, UK
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25
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Abstract
PURPOSE OF REVIEW Reprogramming of gene expression underlies the mechanisms involved in cardiac pathogenesis. MicroRNAs (miRNAs) are unique posttranscriptional regulators of gene expression whose function in cardiac development and disease has recently begun to unravel. In addition, they are potentially highly effective therapeutic tools. In this review, we will summarize the recent advancements in the field. RECENT FINDINGS The cardiac-enriched miRNAs, including miR-1, miR-133, and miR-208, as well as the ubiquitous miR-23a and miR-199b, play major roles in the development of cardiac hypertrophy. On the other hand, miR-21, miR-199a, miR-210, and miR-494 have been proven critical for the myocytes' adaptation and survival during hypoxia/ischemia. Using depletion or replacement strategies against some of these miRNAs has proven very effective in preventing or even reversing some disorders. These findings and more will be detailed in this review. SUMMARY In general, the discovery of miRNAs has uncovered a new dimension of gene regulation that provides us with unique mechanistic insights into cardiac diseases, in addition to which they can be utilized for new diagnostics and therapeutic strategies.
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Ricci M, Lincoln J. Molecular markers of cardiomyopathy in cyanotic pediatric heart disease. PROGRESS IN PEDIATRIC CARDIOLOGY 2011. [DOI: 10.1016/j.ppedcard.2011.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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27
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Abstract
MicroRNAs (miRs) are transcriptionally regulated single-strand RNAs that depress protein expression through posttranscriptional mRNA silencing. A host of recent studies have established essential roles for miRs in cardiac development and cardiac health. Regulated myocardial miR expression is observed in a variety of cardiac syndromes, and serum miR levels are being evaluated as disease biomarkers. The manipulation of miR levels in mouse hearts using genetic techniques or engineered miR mimetics and antagonists is elucidating the roles of specific cardiac miRs in cardiac development, and in the cardiac response to injury or stress, and heart disease. The ability to target multiple factors within a single biological response pathway by a given miR has prompted the development of small miR-targeting molecules that can be readily delivered and have sustained in vivo effects. These advances establish a foundation for novel diagnostics and new therapeutic approaches for myocardial infarction, cardiac hypertrophy, and heart failure.
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Affiliation(s)
- Gerald W Dorn
- Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
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28
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Abstract
Until the middle of the last decade, few people had heard of microRNAs (miRNAs), 21- to 23-nucleotide conserved RNAs. MicroRNAs represent a new paradigm because they regulate most physiological processes and thus have immense potential for medical advancement. Resveratrol, a red wine-derived polyphenolic compound, has been shown to have significant effects in various disease models, such as cardioprotection in ischemic heart, diabetes, and chemoprevention of cancers. The targets of resveratrol include various pathways and molecules, such as sirtuins, FOXOs, and autophagy. The successful application of resveratrol lies in understanding its mechanisms of action through direct and indirect interactions with pathways, including miRNAs. For example, a unique miRNA footprint is present in the heart treated with resveratrol. Targets of those miRNAs have potential implications for physiological and pathophysiological processes in health and disease.
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Affiliation(s)
- Partha Mukhopadhyay
- Laboratory of Physiologic Studies, NIAAA, National Institute of Health, Bethesda, Maryland, USA.
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29
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Response to the Letter by Kumarswamy et al. Circ Res 2010. [DOI: 10.1161/circresaha.110.221515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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