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The Role of ncRNAs in Cardiac Infarction and Regeneration. J Cardiovasc Dev Dis 2023; 10:jcdd10030123. [PMID: 36975887 PMCID: PMC10052289 DOI: 10.3390/jcdd10030123] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
Myocardial infarction is the most prevalent cardiovascular disease worldwide, and it is defined as cardiomyocyte cell death due to a lack of oxygen supply. Such a temporary absence of oxygen supply, or ischemia, leads to extensive cardiomyocyte cell death in the affected myocardium. Notably, reactive oxygen species are generated during the reperfusion process, driving a novel wave of cell death. Consequently, the inflammatory process starts, followed by fibrotic scar formation. Limiting inflammation and resolving the fibrotic scar are essential biological processes with respect to providing a favorable environment for cardiac regeneration that is only achieved in a limited number of species. Distinct inductive signals and transcriptional regulatory factors are key components that modulate cardiac injury and regeneration. Over the last decade, the impact of non-coding RNAs has begun to be addressed in many cellular and pathological processes including myocardial infarction and regeneration. Herein, we provide a state-of-the-art review of the current functional role of diverse non-coding RNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in different biological processes involved in cardiac injury as well as in distinct experimental models of cardiac regeneration.
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Novel Role of miR-18a-5p and Galanin in Rat Lung Ischemia Reperfusion-Mediated Response. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6621921. [PMID: 34497682 PMCID: PMC8420977 DOI: 10.1155/2021/6621921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 07/05/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022]
Abstract
Lung ischemia reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage and is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of the innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNAs) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high-throughput approach and evaluated a distinct set of miRNAs that may play a role in response to IR in rat lung tissue. The top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an in vitro model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. miR-18a-5p plays a role in IR-mediated apoptosis and ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: nuclear factor-erythroid 2-related factor (Nrf2) which in turn may regulate the expression of the miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerated the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p. This study will have important clinical and therapeutic implications for and during transplantation procedures.
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Li C, Wang N, Rao P, Wang L, Lu D, Sun L. Role of the microRNA-29 family in myocardial fibrosis. J Physiol Biochem 2021; 77:365-376. [PMID: 34047925 DOI: 10.1007/s13105-021-00814-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 04/01/2021] [Indexed: 12/11/2022]
Abstract
Myocardial fibrosis (MF) is an inevitable pathological process in the terminal stage of many cardiovascular diseases, often leading to serious cardiac dysfunction and even death. Currently, microRNA-29 (miR-29) is thought to be a novel diagnostic and therapeutic target of MF. Understanding the underlying mechanisms of miR-29 that regulate MF will provide a new direction for MF therapy. In the present review, we concentrate on the underlying signaling pathway of miR-29 affecting MF and the crosstalk regulatory relationship among these pathways to illustrate the complex regulatory network of miR-29 in MF. Additionally, based on our mechanistic understanding, we summarize opportunities and challenges of miR-29-based MF diagnosis and therapy.
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Affiliation(s)
- Changyan Li
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Nan Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Peng Rao
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Limeiting Wang
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China
| | - Di Lu
- Science and Technology Achievement Incubation Center, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China.
| | - Lin Sun
- Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China.
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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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Gomez-Acevedo H, Dai Y, Strub G, Shawber C, Wu JK, Richter GT. Identification of putative biomarkers for Infantile Hemangiomas and Propranolol treatment via data integration. Sci Rep 2020; 10:3261. [PMID: 32094357 PMCID: PMC7039967 DOI: 10.1038/s41598-020-60025-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 12/20/2019] [Indexed: 12/29/2022] Open
Abstract
Infantile hemangiomas (IHs) are the most common benign tumors in early childhood. They show a distinctive mechanism of tumor growth in which a rapid proliferative phase is followed by a regression phase (involution). Propranolol is an approved treatment for IHs, but its mechanism of action remains unclear. We integrated and harmonized microRNA and mRNA transcriptome data from newly generated microarray data on IHs with publicly available data on toxicological transcriptomics from propranolol exposure, and with microRNA data from IHs and propranolol exposure. We identified subsets of putative biomarkers for proliferation and involution as well as a small set of putative biomarkers for propranolol's mechanism of action for IHs, namely EPAS1, LASP1, SLC25A23, MYO1B, and ALDH1A1. Based on our integrative data approach and confirmatory experiments, we concluded that hypoxia in IHs is regulated by EPAS1 (HIF-2α) instead of HIF-1α, and also that propranolol-induced apoptosis in endothelial cells may occur via mitochondrial stress.
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Affiliation(s)
- Horacio Gomez-Acevedo
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Yuemeng Dai
- Mesquite Rehabilitation Institute, Mesquite, Texas, USA
| | - Graham Strub
- Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Carrie Shawber
- Department of Surgery, New York-Presbyterian/Morgan Stanley Children's Hospital, Columbia University, New York, New York, USA
| | - June K Wu
- Department of Reproductive Sciences in Obstetrics & Gynecology and Surgery, Columbia University, New York, New York, USA
| | - Gresham T Richter
- Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Arkansas Children's Hospital, Little Rock, Arkansas, USA
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Kreth S, Hübner M, Hinske LC. MicroRNAs as Clinical Biomarkers and Therapeutic Tools in Perioperative Medicine. Anesth Analg 2018; 126:670-681. [DOI: 10.1213/ane.0000000000002444] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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7
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Rancan L, Simón C, Marchal-Duval E, Casanova J, Paredes SD, Calvo A, García C, Rincón D, Turrero A, Garutti I, Vara E. Lidocaine Administration Controls MicroRNAs Alterations Observed After Lung Ischemia-Reperfusion Injury. Anesth Analg 2017; 123:1437-1447. [PMID: 27870736 DOI: 10.1213/ane.0000000000001633] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) is associated with morbidity and mortality. MicroRNAs (miRNAs) have emerged as regulators of IRI, and they are involved in the pathogenesis of organ rejection. Lidocaine has proven anti-inflammatory activity in several tissues but its modulation of miRNAs has not been investigated. This work aims to investigate the involvement of miRNAs in lung IRI in a lung auto-transplantation model and to investigate the effect of lidocaine. METHODS Three groups (sham, control, and Lidocaine), each comprising 6 pigs, underwent a lung autotransplantation. All groups received the same anesthesia. In addition, animals of lidocaine group received a continuous intravenous administration of lidocaine (1.5 mg/kg/h) during surgery. Lung biopsies were taken before pulmonary artery clamp, before reperfusion, 30 minutes postreperfusion (Rp-30), and 60 minutes postreperfusion (Rp-60). Samples were analyzed for different miRNAs (miR-122, miR-145, miR-146a, miR-182, miR-107, miR-192, miR-16, miR-21, miR-126, miR-127, miR142-5p, miR152, miR155, miR-223, and let7) via the use of reverse-transcription quantitative polymerase chain reaction. Results were normalized with miR-103. RESULTS The expression of miR-127 and miR-16 did not increase after IRI. Let-7d, miR-21, miR-107, miR-126, miR-145, miR-146a, miR-182, and miR-192 significantly increased at the Rp-60 (control versus sham P < .001). miR-142-5p, miR-152, miR-155, and miR 223 significantly increased at the Rp-30 (control versus sham P < .001) and at the Rp-60 (control versus. sham P < .001). The administration of lidocaine was able to attenuate these alterations in a significant way (control versus Lidocaine P < .001). CONCLUSIONS Lung IRI caused dysregulation miRNA. The administration of lidocaine reduced significantly miRNAs alterations.
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Affiliation(s)
- Lisa Rancan
- From the *Department of Biochemistry and Molecular Biology III, Faculty of Medicine, Complutense University of Madrid, Spain; Departments of †Thoracic Surgery and ‡Anesthesiology, Hospital Gregorio Marañón, Madrid, Spain; and Departments of §Physiology and ‖Biostatistics and Operational Investigation, Faculty of Medicine, Complutense University of Madrid, Spain
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Khan AW, Ziemann M, Corcoran SJ, K N H, Okabe J, Rafehi H, Maxwell SS, Esler MD, El-Osta A. NET silencing by let-7i in postural tachycardia syndrome. JCI Insight 2017; 2:e90183. [PMID: 28352654 DOI: 10.1172/jci.insight.90183] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss of function. POTS is characterized by the clinical symptoms of orthostatic intolerance, lightheadedness, tachycardia, and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence that the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with massive parallel sequencing (RICh-seq) we show that let-7i miRNA suppresses NET by methyl-CpG-binding protein 2 (MeCP2). Vorinostat restores epigenetic control and NET expression in leukocytes derived from POTS participants.
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Affiliation(s)
- Abdul Waheed Khan
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.,Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark Ziemann
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Susan J Corcoran
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Harikrishnan K N
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.,Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Jun Okabe
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Haloom Rafehi
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Scott S Maxwell
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Murray D Esler
- Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
| | - Assam El-Osta
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.,Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.,Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.,Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
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Cheng R, Dang R, Zhou Y, Ding M, Hua H. MicroRNA-98 inhibits TGF-β1-induced differentiation and collagen production of cardiac fibroblasts by targeting TGFBR1. Hum Cell 2017; 30:192-200. [PMID: 28251559 DOI: 10.1007/s13577-017-0163-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 01/19/2017] [Indexed: 01/11/2023]
Abstract
To investigate the effects of miR-98 on TGF-β1-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects, HCFs were transfected with miR-98 inhibitor or mimic, and then treated with or without TGF-β1. The level of miR-98 was determined by qRT-PCR in TGF-β1-induced HCFs. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays, respectively. The mRNA and protein expressions of TGFBR1 were determined by qRT-PCR and Western blotting. In this study, the outcomes showed that TGF-β1 could dramatically decrease the level of miR-98 in a time- and concentration-dependent manner. Upregulation of miR-98 dramatically improved TGF-β1-induced increases in cell differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR1 was a potential target gene of miR-98. Luciferase reporter assay demonstrated that miR-98 could directly target TGFBR1. Inhibition of TGFBR1 had the similar effect as miR-98 overexpression. Downregulation of TGFBR1 in HCFs transfected with miR-98 inhibitor partially reversed the protective effect of miR-98 overexpression on TGF-β1-induced cardiac fibrosis in HCFs. Upregulation of miR-98 ameliorates TGF-β1-induced differentiation and collagen accumulation of HCFs by downregulation of TGFBR1. These results provide further evidence for protective effect of miR-98 overexpression on TGF-β1-induced cardiac fibrosis.
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Affiliation(s)
- Ranran Cheng
- Affiliated Hospital, Medical Department, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China.
- College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China.
| | - Ruiying Dang
- Emergency Department, Affiliated Hospital, Hebei University of Engineering, Congtai Road No. 81, Handan, 056002, Hebei, People's Republic of China
| | - Yan Zhou
- Affiliated Hospital, Medical Department, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China
- College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China
| | - Min Ding
- College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China
| | - Huikun Hua
- College of Medicine, Hebei University of Engineering, Handan, 056002, Hebei, People's Republic of China
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Chimenti I, Pagano F, Cavarretta E, Angelini F, Peruzzi M, Barretta A, Greco E, De Falco E, Marullo AGM, Sciarretta S, Biondi-Zoccai G, Frati G. Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells. Sci Rep 2016; 6:36774. [PMID: 27841293 PMCID: PMC5107949 DOI: 10.1038/srep36774] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 10/20/2016] [Indexed: 02/08/2023] Open
Abstract
Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding yield and phenotype of cardiospheres (CSs) and CS-derived cells (CDCs), which are a clinically relevant population for cell therapy, containing progenitors. We describe a statistically significant association between BB therapy and improved CSs yield and CDCs phenotype. We show that BB-CDCs have a reduced fibrotic-like CD90 + subpopulation, with reduced expression of collagen-I and increased expression of cardiac genes, compared to CDCs from non-BB donors. Moreover BB-CDCs had a distinctive microRNA expression profile, consistent with reduced fibrotic features (miR-21, miR-29a/b/c downregulation), and enhanced regenerative potential (miR-1, miR-133, miR-101 upregulation) compared to non-BB. In vitro adrenergic pharmacological treatments confirmed cytoprotective and anti-fibrotic effects of β1-blocker on CDCs. This study shows anti-fibrotic and pro-commitment effects of BB treatment on endogenous cardiac reparative cells, and suggests adjuvant roles of β-blockers in cell therapy applications.
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Affiliation(s)
- Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Francesca Pagano
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Elena Cavarretta
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Francesco Angelini
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Mariangela Peruzzi
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Antonio Barretta
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological, and Geriatric Sciences, “Umberto I” Hospital, “La Sapienza” University of Rome, Italy
| | - Ernesto Greco
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological, and Geriatric Sciences, “Umberto I” Hospital, “La Sapienza” University of Rome, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Antonino G. M. Marullo
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
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Strub GM, Kirsh AL, Whipple ME, Kuo WP, Keller RB, Kapur RP, Majesky MW, Perkins JA. Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma. JCI Insight 2016; 1:e88856. [PMID: 27660822 DOI: 10.1172/jci.insight.88856] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Infantile hemangioma (IH) is the most common vascular tumor of infancy, and it uniquely regresses in response to oral propranolol. MicroRNAs (miRNAs) have emerged as key regulators of vascular development and are dysregulated in many disease processes, but the role of miRNAs in IH growth has not been investigated. We report expression of C19MC, a primate-specific megacluster of miRNAs expressed in placenta with rare expression in postnatal tissues, in glucose transporter 1-expressing (GLUT-1-expressing) IH endothelial cells and in the plasma of children with IH. Tissue or circulating C19MC miRNAs were not detectable in patients having 9 other types of vascular anomalies or unaffected children, identifying C19MC miRNAs as the first circulating biomarkers of IH. Levels of circulating C19MC miRNAs correlated with IH tumor size and propranolol treatment response, and IH tissue from children treated with propranolol or from children with partially involuted tumors contained lower levels of C19MC miRNAs than untreated, proliferative tumors, implicating C19MC miRNAs as potential drivers of IH pathogenesis. Detection of C19MC miRNAs in the circulation of infants with IH may provide a specific and noninvasive means of IH diagnosis and identification of candidates for propranolol therapy as well as a means to monitor treatment response.
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Affiliation(s)
- Graham M Strub
- Department of Otolaryngology - Head and Neck Surgery, University of Washington, Seattle, Washington, USA
| | - Andrew L Kirsh
- Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington, USA
| | - Mark E Whipple
- Department of Otolaryngology - Head and Neck Surgery, University of Washington, Seattle, Washington, USA
| | - Winston P Kuo
- Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts, USA.,Predicine Inc., Hayward, California, USA
| | - Rachel B Keller
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Raj P Kapur
- Department of Laboratories, Seattle Children's Hospital (SCH), Seattle, Washington, USA
| | - Mark W Majesky
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA
| | - Jonathan A Perkins
- Department of Otolaryngology - Head and Neck Surgery, University of Washington, Seattle, Washington, USA.,Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington, USA
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13
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Zhou Y, Chen Q, Lew KS, Richards AM, Wang P. Discovery of Potential Therapeutic miRNA Targets in Cardiac Ischemia-Reperfusion Injury. J Cardiovasc Pharmacol Ther 2015; 21:296-309. [PMID: 26396139 DOI: 10.1177/1074248415604463] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/14/2015] [Indexed: 11/17/2022]
Abstract
BACKGROUND A highly efficient approach to select microRNA (miRNA) targets is a key to develop a miRNA-based therapeutic approach to cardiac ischemia-reperfusion (I/R). To reverse the change induced by disease, I/R in this case, is the traditional strategy to develop therapeutic drugs. However, examples show that it will not always serve the purpose. In this study, we demonstrate an additional approach of selecting miRNA targets with therapeutic potential following cues from cardioprotection-induced changes rather than by reversing disease-induced changes in cardiac I/R. METHODS Isolated perfused rat hearts subjected to I/R were treated with 50 μmol/L sodium hydrosulfide (NaHS) or 10 nmol/L urocortin 2 (UCN2). Cardiac miRNA regulations were determined by miRNA array. Functional screening of selected miRNA mimics, assessed by WST (2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) activity and lactate dehydrogenase (LDH) release, was performed in H9c2 and neonatal rat ventricular myocytes (NRVMs) with hypoxia/reoxygenation. RNA-induced silencing complex (RISC)-loaded miRNAs caused by mimic transfection were quantified following argonaute-2 immunoprecipitation. Gene regulations of 1 selected miRNA were determined by quantitative polymerase chain reaction and Western blot. RESULTS Treatment with NaHS and UCN2 significantly improved cardiac function and reduced LDH release. The miRNA array indicated a panel of commonly up- and downregulated miRNAs. Among them, 10 upregulated miRNAs with antiapoptotic and antiautophagy potentials were selected for further screening. Mimics of miRNA-221, -150, and -206 were protective in both H9c2 and NRVM. RISC-loaded miRNAs were up by ∼20-fold above. To further prove the feasibility of this approach, miRNA-221 was studied. It reduced I/R-induced caspase 3/7 activity and LC3-II (microtubule-associated protein 1 light chain 3). Measuring genes predicted to regulate apoptosis and autophagy, miRNA-221 mimic decreased Ddit4, TP53inp1, and p27 at both messenger RNA (mRNA) and protein levels, and reduced mRNA of Bak1 and Puma and proteins of Bim and Bmf. CONCLUSION Mimicking miRNA changes caused by cardioprotective agents, combined with functional screening, enables investigators to efficiently identify novel miRNAs with therapeutic potential in cardiac I/R.
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Affiliation(s)
- Yue Zhou
- Cardiovascular Research Institute, National University Health System, National University of Singapore, Singapore Department of Medicine, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
| | - Qiying Chen
- Huashan Hospital, Fudan University, Shanghai, China
| | - Kar Sheng Lew
- Cardiovascular Research Institute, National University Health System, National University of Singapore, Singapore Department of Medicine, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
| | - A Mark Richards
- Cardiovascular Research Institute, National University Health System, National University of Singapore, Singapore Department of Medicine, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore Department of Medicine, Christchurch Heart Institute, University of Otago, Christ Church, New Zealand Cardiac Department, National University Health System, Singapore
| | - Peipei Wang
- Cardiovascular Research Institute, National University Health System, National University of Singapore, Singapore Department of Medicine, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
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14
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Abstract
It is well established that cardiac remodeling plays a pivotal role in the development of heart failure, a leading cause of death worldwide. Meanwhile, sympathetic hyperactivity is an important factor in inducing cardiac remodeling. Therefore, an in-depth understanding of beta-adrenoceptor signaling pathways would help to find better ways to reverse the adverse remodeling. Here, we reviewed five pathways, namely mitogen-activated protein kinase signaling, Gs-AC-cAMP signaling, Ca(2+)-calcineurin-NFAT/CaMKII-HDACs signaling, PI3K signaling and beta-3 adrenergic signaling, in cardiac remodeling. Furthermore, we constructed a cardiac-remodeling-specific regulatory network including miRNA, transcription factors and target genes within the five pathways. Both experimental and clinical studies have documented beneficial effects of beta blockers in cardiac remodeling; nevertheless, different blockers show different extent of therapeutic effect. Exploration of the underlying mechanisms could help developing more effective drugs. Current evidence of treatment effect of beta blockers in remodeling was also reviewed based upon information from experimental data and clinical trials. We further discussed the mechanism of how beta blockers work and why some beta blockers are more potent than others in treating cardiac remodeling within the framework of cardiac remodeling network.
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15
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Novel biomarkers in cardiology: MicroRNAs in atrial fibrillation. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2015; 85:225-9. [DOI: 10.1016/j.acmx.2015.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/02/2015] [Accepted: 01/16/2015] [Indexed: 11/20/2022] Open
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16
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Ghasemi O, Ma Y, Lindsey ML, Jin YF. Using systems biology approaches to understand cardiac inflammation and extracellular matrix remodeling in the setting of myocardial infarction. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2014; 6:77-91. [PMID: 24741709 DOI: 10.1002/wsbm.1248] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Inflammation and extracellular matrix (ECM) remodeling are important components regulating the response of the left ventricle to myocardial infarction (MI). Significant cellular- and molecular-level contributors can be identified by analyzing data acquired through high-throughput genomic and proteomic technologies that provide expression levels for thousands of genes and proteins. Large-scale data provide both temporal and spatial information that need to be analyzed and interpreted using systems biology approaches in order to integrate this information into dynamic models that predict and explain mechanisms of cardiac healing post-MI. In this review, we summarize the systems biology approaches needed to computationally simulate post-MI remodeling, including data acquisition, data analysis for biomarker classification and identification, data integration to build dynamic models, and data interpretation for biological functions. An example for applying a systems biology approach to ECM remodeling is presented as a reference illustration.
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17
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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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18
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Hao M, Zang M, Wendlandt E, Xu Y, An G, Gong D, Li F, Qi F, Zhang Y, Yang Y, Zhan F, Qiu L. Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma. Int J Cancer 2014; 136:1835-44. [PMID: 25220540 DOI: 10.1002/ijc.29199] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 07/18/2014] [Accepted: 08/15/2014] [Indexed: 01/03/2023]
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the clonal expansion of plasma cells. Despite continuing advances, novel biomarkers are needed for diagnosis and prognosis of MM. In our study, we characterized the diagnostic and prognostic potential of circulating microRNAs (miRNAs) in MM. Serum miRNA levels were analyzed in 108 newly diagnosed symptomatic MM patients and 56 healthy donors (HDs). Our analysis identified 95 dysregulated miRNAs in newly diagnosed MM patients. Of the 95 dysregulated miRNAs, dysregulation of miR-19a, miR-92a, miR-214-3p, miR-135b-5p, miR-4254, miR-3658 and miR-33b was confirmed by quantitative reverse transcription PCR (RT-qPCR). Receiver operating characteristic analysis revealed that a combination of miR-19a and miR-4254 can distinguish MM from HD with a sensitivity of 91.7% and specificity of 90.5%. Decreased expression of miR-19a was positively correlated with international staging system advancement, del(13q14) and 1q21 amplification. Furthermore, downregulation of miR-19a resulted in significantly decreased progression-free survival (PFS) and overall survival (OS). Our analysis indicated that the poor prognostic correlation of miR-19a expression was independent of genetic abnormalities in MM. Multivariate analysis revealed that miR-19a was a significant predictor of shortened PFS and OS. Interestingly, although miR-19a levels portend a poor prognosis, patients with low miR-19a levels had an improved response to bortezomib compared to those with high miR-19a profile. Patients with downregulated miR-19a experienced a significantly extended survival upon bortezomib-based therapy. These data demonstrate that the expression patterns of serum microRNAs are altered in MM, and miR-19a levels are a valuable prognostic marker to identify high-risk MM.
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Affiliation(s)
- Mu Hao
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
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19
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Xu C, Hu Y, Hou L, Ju J, Li X, Du N, Guan X, Liu Z, Zhang T, Qin W, Shen N, Bilal MU, Lu Y, Zhang Y, Shan H. β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J Mol Cell Cardiol 2014; 75:111-21. [PMID: 25066695 DOI: 10.1016/j.yjmcc.2014.07.009] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Revised: 06/26/2014] [Accepted: 07/15/2014] [Indexed: 01/04/2023]
Abstract
Oxidative stress is a causal factor and key promoter of a variety of cardiovascular diseases associated with apoptotic cell death by causing deregulation of related genes. Though carvedilol, a β-adrenergic blocker, has been shown to produce cytoprotective effects against cardiomyocyte apoptosis, the mechanisms are not fully understood. The present study was designed to investigate whether the beneficial effects of carvedilol are related to microRNAs which have emerged as critical players in cardiovascular pathophysiology via post-transcriptional regulation of protein-coding genes. In vivo, we demonstrated that carvedilol ameliorated impaired cardiac function of infarct rats and restored miR-133 expression. In vitro, carvedilol protected cardiomyocytes from H2O2 induced apoptosis detected by TUNEL staining and MTT assays, and increased miR-133 expression in cardiomyocytes. Overexpression of miR-133, a recognized anti-apoptotic miRNA, produced similar effects to carvedilol: reduction of reactive oxygen species (ROS) and malondialdehyde (MDA) content and increment of superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) level, so as to protect cardiomyocytes from apoptosis by downregulating caspase-9 and caspase-3 expression in the presence of H2O2. Transfection with AMO-133 (antisense inhibitor oligodeoxyribonucleotides) alone abolished the beneficial effects of carvedilol. Caspase-9-specific inhibitor z-LEHD-fmk, caspase-3-specific inhibitor z-DEVD-fmk, caspase-9 siRNA and caspase-3 siRNA were used to establish caspase-3 as a downstream target of miR-133. In conclusion, our data indicated that carvedilol protected cardiomyocytes by increasing miR-133 expression and suppressing caspase-9 and subsequent apoptotic pathways.
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Affiliation(s)
- Chaoqian Xu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yingying Hu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Liangyu Hou
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Jin Ju
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiaoguang Li
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Ning Du
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiaoxiang Guan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Zhenhong Liu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Tianze Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, China
| | - Wei Qin
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Nannan Shen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Muhammad U Bilal
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China
| | - Yanjie Lu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yong Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China.
| | - Hongli Shan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China.
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20
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Molecular evidence of stress-induced acute heart injury in a mouse model simulating posttraumatic stress disorder. Proc Natl Acad Sci U S A 2014; 111:3188-93. [PMID: 24516145 DOI: 10.1073/pnas.1400113111] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Posttraumatic stress disorder (PTSD) is a common condition induced by life-threatening stress, such as that experienced by soldiers under battlefield conditions. Other than the commonly recognized behavioral and psychological dysfunction, epidemiological studies have also revealed that PTSD patients have a higher risk of other diseases, such as cardiovascular disorders. Using a PTSD mouse model, we investigated the longitudinal transcriptomic changes in heart tissues after the exposure to stress through intimidation. Our results revealed acute heart injury associated with the traumatic experience, reflecting the underlying biological injury processes of the immune response, extracellular matrix remodeling, epithelial-to-mesenchymal cell transitions, and cell proliferation. Whether this type of injury has any long-term effects on heart function is yet to be determined. The differing responses to stress leading to acute heart injury in different inbred strains of mice also suggest that this response has a genetic as well as an environmental component. Accordingly, the results from this study suggest a molecular basis for the observed higher risk of cardiovascular disorders in PTSD patients, which raises the likelihood of cardiac dysfunction induced by long-term stress exposures.
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21
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Liao XB, Zhang ZY, Yuan K, Liu Y, Feng X, Cui RR, Hu YR, Yuan ZS, Gu L, Li SJ, Mao DA, Lu Q, Zhou XM, de Jesus Perez VA, Yuan LQ. MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells. Endocrinology 2013; 154:3344-52. [PMID: 23798596 DOI: 10.1210/en.2012-2236] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with β-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3'-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.
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MESH Headings
- 3' Untranslated Regions/drug effects
- Animals
- Biomarkers/metabolism
- Cell Transdifferentiation/drug effects
- Cells, Cultured
- Core Binding Factor Alpha 1 Subunit/antagonists & inhibitors
- Core Binding Factor Alpha 1 Subunit/biosynthesis
- Core Binding Factor Alpha 1 Subunit/genetics
- Core Binding Factor Alpha 1 Subunit/metabolism
- Female
- Gene Silencing
- Genes, Reporter/drug effects
- Glycerophosphates/metabolism
- Mice
- Mice, Inbred C57BL
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Mutation
- Oligonucleotides, Antisense/adverse effects
- Osteoblasts/drug effects
- Osteoblasts/metabolism
- Osteoblasts/pathology
- Osteocalcin/metabolism
- Recombinant Proteins/antagonists & inhibitors
- Recombinant Proteins/biosynthesis
- Recombinant Proteins/metabolism
- Vascular Calcification/chemically induced
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
- Vascular Calcification/prevention & control
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Affiliation(s)
- Xiao-Bo Liao
- Departments of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, People’s Republic of China
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22
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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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23
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Zhu W, Zhao Y, Xu Y, Sun Y, Wang Z, Yuan W, Du Z. Dissection of protein interactomics highlights microRNA synergy. PLoS One 2013; 8:e63342. [PMID: 23691029 PMCID: PMC3653946 DOI: 10.1371/journal.pone.0063342] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 04/01/2013] [Indexed: 11/18/2022] Open
Abstract
Despite a large amount of microRNAs (miRNAs) have been validated to play crucial roles in human biology and disease, there is little systematic insight into the nature and scale of the potential synergistic interactions executed by miRNAs themselves. Here we established an integrated parameter synergy score to determine miRNA synergy, by combining the two mechanisms for miRNA-miRNA interactions, miRNA-mediated gene co-regulation and functional association between target gene products, into one single parameter. Receiver operating characteristic (ROC) analysis indicated that synergy score accurately identified the gene ontology-defined miRNA synergy (AUC = 0.9415, p<0.001). Only a very small portion of the random miRNA-miRNA combinations generated potent synergy, implying poor expectancy of widespread synergy. However, targeting more key genes made two miRNAs more likely to act synergistically. Compared to other miRNAs, miR-21 was a highly exceptional case due to frequent appearance in the top synergistic miRNA pairs. This result highlighted its essential role in coordinating or strengthening physiological and pathological functions of other miRNAs. The synergistic effect of miR-21 and miR-1 were functionally validated for their significant influences on myocardial apoptosis, cardiac hypertrophy and fibrosis. The novel approach established in this study enables easy and effective identification of condition-restricted potent miRNA synergy simply by concentrating the available protein interactomics and miRNA-target interaction data into a single parameter synergy score. Our results may be important for understanding synergistic gene regulation by miRNAs and may have significant implications for miRNA combination therapy of cardiovascular disease.
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Affiliation(s)
- Wenliang Zhu
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yilei Zhao
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yingqi Xu
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yong Sun
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhe Wang
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei Yuan
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhimin Du
- Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- * E-mail:
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24
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Tao H, Shi KH, Yang JJ, Huang C, Liu LP, Li J. Epigenetic regulation of cardiac fibrosis. Cell Signal 2013; 25:1932-8. [PMID: 23602934 DOI: 10.1016/j.cellsig.2013.03.024] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 03/01/2013] [Accepted: 03/28/2013] [Indexed: 02/05/2023]
Abstract
Cardiac fibrosis is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal function. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic modifications impact on the development of cardiac fibrosis. Epigenetic modifications control cell proliferation, differentiation, migration, and so on. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and silencing by microRNAs. We here outline the recent work pertaining to epigenetic changes in cardiac fibrosis. This review focuses on the epigenetic regulation of cardiac fibrosis.
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Affiliation(s)
- Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei 230601, China
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25
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Ye H, Ling S, Castillo AC, Thomas B, Long B, Qian J, Perez-Polo JR, Ye Y, Chen X, Birnbaum Y. Nebivolol induces distinct changes in profibrosis microRNA expression compared with atenolol, in salt-sensitive hypertensive rats. Hypertension 2013; 61:1008-13. [PMID: 23460283 DOI: 10.1161/hypertensionaha.111.00892] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Nebivolol is a selective β1-blocker with nitric oxide-enhancing effects. MicroRNAs are small noncoding RNA molecules that downregulate gene expression. We compared the effects of nebivolol and atenolol, a first generation β1-selective blocker, on left ventricular hypertrophy, fibrosis, and function and microRNA expression in a rodent model of hypertension. Dahl salt-sensitive rats received either low-salt chow (control) or AIN-76A high-salt (8% NaCl) diet and randomized to vehicle (high-salt), nebivolol (20 mg/kg per day), or atenolol (50 mg/kg per day) for 8 weeks. High-salt induced left ventricular hypertrophy and fibrosis and decreased the expression of miR-27a, -29a, and -133a. Nebovolol attenuated deterioration of left ventricular systolic function, remodeling, and fibrosis more than atenolol, despite similar effects on heart rate and blood pressure. Nebivolol, but not atenolol, prevented the decrease in miR-27a and -29a induced by high-salt. Nebivolol and atenolol equally attenuated the decrease in miR-133a. In vitro overexpression of miR-27a,-29a, and -133a inhibited cardiomyocyte hypertrophy and reduced collagen expression. Both miR-27a and -29a target Sp1, and miR-133a targets Cdc42. Pharmacological inhibition of Sp1 and Cdc42 decreased myocardial fibrosis and hypertrophy. Our data support a differential microRNAs expression profile in salt-induced hypertension. Nebivolol substantially attenuated cardiac remodeling, hypertrophy, and fibrosis more than atenolol. These effects are related to attenuation of the hypertension-induced decrease in miR-27a and -29a (with a subsequent decrease in Sp1 expression) and miR-133a (with a subsequent decrease in Cdc42).
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Affiliation(s)
- Hongmei Ye
- State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing, People’s Republic of China
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26
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Duarte JD. A Look to the Future. Pharmacogenomics 2013. [DOI: 10.1016/b978-0-12-391918-2.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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27
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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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Boštjančič E, Zidar N, Glavač D. MicroRNAs and cardiac sarcoplasmic reticulum calcium ATPase-2 in human myocardial infarction: expression and bioinformatic analysis. BMC Genomics 2012; 13:552. [PMID: 23066896 PMCID: PMC3532181 DOI: 10.1186/1471-2164-13-552] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 09/13/2012] [Indexed: 01/19/2023] Open
Abstract
Background Cardiac sarco(endo)plasmic reticulum calcium ATPase-2 (SERCA2) plays one of the central roles in myocardial contractility. Both, SERCA2 mRNA and protein are reduced in myocardial infarction (MI), but the correlation has not been always observed. MicroRNAs (miRNAs) act by targeting 3'-UTR mRNA, causing translational repression in physiological and pathological conditions, including cardiovascular diseases. One of the aims of our study was to identify miRNAs that could influence SERCA2 expression in human MI. Results The protein SERCA2 was decreased and 43 miRNAs were deregulated in infarcted myocardium compared to corresponding remote myocardium, analyzed by western blot and microRNA microarrays, respectively. All the samples were stored as FFPE tissue and in RNAlater. miRNAs binding prediction to SERCA2 including four prediction algorithms (TargetScan, PicTar, miRanda and mirTarget2) identified 213 putative miRNAs. TAM and miRNApath annotation of deregulated miRNAs identified 18 functional and 21 diseased states related to heart diseases, and association of the half of the deregulated miRNAs to SERCA2. Free-energy of binding and flanking regions (RNA22, RNAfold) was calculated for 10 up-regulated miRNAs from microarray analysis (miR-122, miR-320a/b/c/d, miR-574-3p/-5p, miR-199a, miR-140, and miR-483), and nine miRNAs deregulated from microarray analysis were used for validation with qPCR (miR-21, miR-122, miR-126, miR-1, miR-133, miR-125a/b, and miR-98). Based on qPCR results, the comparison between FFPE and RNAlater stored tissue samples, between Sybr Green and TaqMan approaches, as well as between different reference genes were also performed. Conclusion Combing all the results, we identified certain miRNAs as potential regulators of SERCA2; however, further functional studies are needed for verification. Using qPCR, we confirmed deregulation of nine miRNAs in human MI, and show that qPCR normalization strategy is important for the outcome of miRNA expression analysis in human MI.
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Affiliation(s)
- Emanuela Boštjančič
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, Ljubljana, Slovenia
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Role of microRNAs in cardiac remodelling: new insights and future perspectives. Int J Cardiol 2012; 167:1651-9. [PMID: 23063140 DOI: 10.1016/j.ijcard.2012.09.120] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 09/20/2012] [Accepted: 09/22/2012] [Indexed: 01/08/2023]
Abstract
Cardiac remodelling is a key process in the progression of cardiovascular disease, implemented in myocardial infarction, valvular heart disease, myocarditis, dilated cardiomyopathy, atrial fibrillation and heart failure. Fibroblasts, extracellular matrix proteins, coronary vasculature, cardiac myocytes and ionic channels are all involved in this remodelling process. MicroRNAs (miRNAs) represent a sizable sub-group of small non-coding RNAs, which degrade or inhibit the translation of their target mRNAs, thus regulating gene expression and play an important role in a wide range of biologic processes. Recent studies have reported that miRNAs are aberrantly expressed in the cardiovascular system under some pathological conditions. Indeed, in vitro and in vivo models have revealed that miRNAs are essential for cardiac development and remodelling. Clinically, there is increasing evidence of the potential diagnostic role of miRNAs as potential diagnostic biomarkers and they may represent a novel therapeutic target in several cardiovascular disorders. This paper provides an overview of the impact of several miRNAs in electrical and structural remodelling of the cardiac tissue, and the diagnostic and therapeutic potential of miRNA in cardiovascular disease.
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Abstract
PURPOSE OF REVIEW We will review the role of microRNAs (miRNAs), small noncoding RNAs with regulatory function, in myocardial infarction (MI). Specifically, we will examine the effect of MI on miRNAs' expression in the heart, the effect of MI on circulating miRNAs, which miRNAs' overexpression or downmodulation appears to have a therapeutic role in MI and which cardiac miRNAs are modulated by drugs/experimental molecules/cell transplantation strategies which have an established or potential therapeutic role in MI. RECENT FINDINGS A rapidly increasing number of studies are showing that cardiac and circulating miRNAs are markedly altered in MI. These novel findings shed new light on the mechanisms that lead to MI complications, post-MI ventricular remodeling and cardiac repair. Further, recent studies show that circulating miRNAs may represent novel and sensitive biomarkers of MI and, possibly, also an intercellular signaling mechanism. Overexpression and downregulation of specific miRNAs are being evaluated as a novel approach to the treatment of MI. Finally, it appears that some established and potential MI therapies (approved drugs/experimental molecules/cell therapy interventions) may act, at least in part, via modulation of specific miRNAs. SUMMARY Although miRNAs' role in MI is still largely uncharacterized, recent studies suggest that miRNAs may represent novel therapeutic targets and MI biomarkers.
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Schroen B, Heymans S. Small but smart--microRNAs in the centre of inflammatory processes during cardiovascular diseases, the metabolic syndrome, and ageing. Cardiovasc Res 2011; 93:605-13. [PMID: 21994347 DOI: 10.1093/cvr/cvr268] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
With a progressively growing elderly population, ageing-associated pathologies such as cardiovascular diseases are becoming an increasing economic, social, and personal burden for Western societies. Interestingly, all ageing-associated diseases share a common denominator: inflammation. Recently, microRNAs were shown to be implicated in the full range of processes of ageing, inflammation, and cardiovascular diseases. This review focuses on their role in cardiovascular diseases with emphasis on their implication in the inflammatory processes that accompany heart failure, atherosclerosis, coronary artery disease, and finally obesity and diabetes as components of the ageing-associated metabolic syndrome.
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Affiliation(s)
- Blanche Schroen
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands
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