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Yang Y, Chen Y, Tang JY, Chen J, Li GQ, Feng B, Mu J. MiR-29a-3p inhibits fibrosis of diabetic kidney disease in diabetic mice via downregulation of DNA methyl transferase 3A and 3B. World J Diabetes 2025; 16:93630. [DOI: 10.4239/wjd.v16.i4.93630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 09/16/2024] [Accepted: 01/20/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND At present, the incidence of diabetic nephropathy is increasing year by year, and there are many studies on the pathogenesis of diabetic nephropathy, but it is still not completely clear. The final pathological result of diabetic nephropathy is mainly glomerular cell fibrosis, and the roles of micro-RNA (miRNA)-29 and DNA methyl transferase (DNMTs) in cell fibrosis have been confirmed in other studies, but there is a lack of relevant research in the kidney at present.
AIM To study the potential involvement of miRNA-29a-3p in fibrosis related to diabetic kidney disease (DKD).
METHODS The expression of miR-29a-3p, DNMT3A/3B, fibrosis-related molecules, Wnt3a, β-catenin, Janus kinase 2, and signal transducer and activator of transcription 3 was assessed in SV40MES13 cells and diabetic mice using quantitative real-time PCR and western blotting. Furthermore, the expression changes of fibrosis-related molecules were further analyzed using immunofluorescence and immunohistochemical blotting. The renal pathological changes of DKD in each group were also studied using hematoxylin-eosin and periodate-Schiff reaction staining.
RESULTS In both the in vivo and in vitro experiments, it was observed that high glucose induction significantly decreased miR-29a-3p expression. As a result of this downregulation, DKD-related fibrosis was found to be promoted, as confirmed by elevated expression levels of α-smooth muscle actin, collagen type I, and fibronectin. MiR-29a-3p targets the 3’ non-coding regions of DNMT3A and DNMT3B and inhibits their expression. Inhibition of DNMT3A and DNMT3B can reverse the effect of miR-29a-3p downregulation on DKD-related fibrosis.
CONCLUSION MiR-29a-3p can regulate Wnt/β-catenin and Janus kinase/signal transducer and activator of transcription signal pathways by regulating and inhibiting the expression of DNMT3A/3B and thus participate in the inhibition of DKD-related fibrosis.
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Affiliation(s)
- Ying Yang
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Yi Chen
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Jian-Ying Tang
- Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
| | - Jian Chen
- Institute of Immunology, The Third Military Medical University, Chongqing 400038, China
| | - Gui-Qing Li
- Institute of Immunology, The Third Military Medical University, Chongqing 400038, China
| | - Bing Feng
- Department of Nephrology, Third Military Medical University, Chongqing 400038, China
| | - Jiao Mu
- Department of Nephrology, Chongqing Medical University, Chongqing 401331, China
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2
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Chen Y, Wang X, Na X, Zhang Y, Cai L, Song J, Yang C. DMF-DM-seq: Digital-Microfluidics Enabled Dual-Modality Sequencing of Single-Cell mRNA and microRNA with High Integration, Sensitivity, and Automation. Anal Chem 2024; 96:12916-12926. [PMID: 39038243 DOI: 10.1021/acs.analchem.4c03378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Multimodal measurement of single cells provides deep insights into the intricate relationships between individual molecular layers and the regulatory mechanisms underlying intercellular variations. Here, we reported DMF-DM-seq, a highly integrated, sensitive, and automated platform for single-cell mRNA and microRNA (miRNA) co-sequencing based on digital microfluidics. This platform first integrates the processes of single-cell isolation, lysis, component separation, and simultaneous sequencing library preparation of mRNA and miRNA within a single DMF device. Compared with the current half-cell measuring strategy, DMF-DM-seq enables complete separation of single-cell mRNA and miRNA via a magnetic field application, resulting in a higher miRNA detection ability. DMF-DM-seq revealed differential expression patterns of single cells of noncancerous breast cells and noninvasive and aggressive breast cancer cells at both mRNA and miRNA levels. The results demonstrated the anticorrelated relationship between miRNA and their mRNA targets. Further, we unravel the tumor growth and metastasis-associated biological processes enriched by miRNA-targeted genes, along with important miRNA-interaction networks involved in significant signaling pathways. We also deconstruct the miRNA regulatory mechanisms underlying different signaling pathways across different breast cell types. In summary, DMF-DM-seq offers a powerful tool for a comprehensive study of the expression heterogeneity of single-cell mRNA and miRNA, which will be widely applied in basic and clinical research.
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Affiliation(s)
- Yingwen Chen
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Xuanqun Wang
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Xing Na
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Yingkun Zhang
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Linfeng Cai
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
| | - Jia Song
- Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chaoyong Yang
- State Key Laboratory for Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Key Laboratory of Analytical Chemistry, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, No. 55, Zhenhai Road, Siming District, Xiamen 361003, China
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Jiao W, Hao J, Liu JM, Gao WN, Zhao JJ, Li YJ. Mesenchymal stem cells-derived extracellular vesicle-incorporated H19 attenuates cardiac remodeling in rats with heart failure. Kaohsiung J Med Sci 2024; 40:46-62. [PMID: 37885317 DOI: 10.1002/kjm2.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/12/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Cardiac remodeling is manifested by hypertrophy and apoptosis of cardiomyocytes, resulting in the progression of cardiovascular diseases. Long noncoding RNAs (lncRNAs) serve as modifiers of cardiac remodeling. In this study, we aimed to explore the molecular mechanism of H19 shuttled by mesenchymal stem cells (MSC)-derived extracellular vesicles (EV) in cardiac remodeling upon heart failure (HF). Using the GEO database, H19, microRNA (miR)-29b-3p, and CDC42 were screened out as differentially expressed biomolecules in HF. H19 and CDC42 were elevated, and miR-29b-3p was decreased after MSC-EV treatment in rats subjected to ligation of the coronary artery. MSC-EV alleviated myocardial injury in rats with HF. H19 downregulation exacerbated myocardial injury, while miR-29b-3p inhibitor alleviated myocardial injury. By contrast, CDC42 downregulation aggravated the myocardial injury again. PI3K/AKT pathway was activated by MSC-EV. These findings provide insights into how H19 shuttled by EV mitigates cardiac remodeling through a competitive endogenous RNA network regarding miR-29b-3p and CDC42.
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Affiliation(s)
- Wei Jiao
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jie Hao
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jin-Ming Liu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Wei-Nian Gao
- Department of Cardiac Macrovascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jia-Jia Zhao
- Graduate Academy of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Yong-Jun Li
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
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Bakopoulos D, Golenkina S, Dark C, Christie EL, Sánchez-Sánchez BJ, Stramer BM, Cheng LY. Convergent insulin and TGF-β signalling drives cancer cachexia by promoting aberrant fat body ECM accumulation in a Drosophila tumour model. EMBO Rep 2023; 24:e57695. [PMID: 38014610 DOI: 10.15252/embr.202357695] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/16/2023] [Accepted: 10/26/2023] [Indexed: 11/29/2023] Open
Abstract
In this study, we found that in the adipose tissue of wildtype animals, insulin and TGF-β signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, Sog also modulates TGF-β signalling to regulate ECM accumulation in the fat body. TGF-β signalling causes ECM retention in the fat body and subsequently depletes muscles of fat body-derived ECM proteins. Activation of insulin signalling, inhibition of TGF-β signalling, or modulation of ECM levels via SPARC, Rab10 or Collagen IV in the fat body, is able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.
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Affiliation(s)
- Daniel Bakopoulos
- Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
| | | | - Callum Dark
- Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
| | - Elizabeth L Christie
- Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
| | | | - Brian M Stramer
- Kings College London, Randall Centre for Cell & Molecular Biophysics, London, UK
| | - Louise Y Cheng
- Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic, Australia
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Vic, Australia
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5
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Cardiovascular Disease-Associated MicroRNAs as Novel Biomarkers of First-Trimester Screening for Gestational Diabetes Mellitus in the Absence of Other Pregnancy-Related Complications. Int J Mol Sci 2022; 23:ijms231810635. [PMID: 36142536 PMCID: PMC9501303 DOI: 10.3390/ijms231810635] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.
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6
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Holder ER, Alibhai FJ, Caudle SL, McDermott JC, Tobin SW. The importance of biological sex in cardiac cachexia. Am J Physiol Heart Circ Physiol 2022; 323:H609-H627. [PMID: 35960634 DOI: 10.1152/ajpheart.00187.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cardiac cachexia is a catabolic muscle wasting syndrome observed in approximately 1 in 10 heart failure patients. Increased skeletal muscle atrophy leads to frailty and limits mobility which impacts quality of life, exacerbates clinical care, and is associated with higher rates of mortality. Heart failure is known to exhibit a wide range of prevalence and severity when examined across individuals of different ages and with co-morbidities related to diabetes, renal failure and pulmonary dysfunction. It is also recognized that men and women exhibit striking differences in the pathophysiology of heart failure as well as skeletal muscle homeostasis. Given that both skeletal muscle and heart failure physiology are in-part sex dependent, the diagnosis and treatment of cachexia in heart failure patients may depend on a comprehensive examination of how these organs interact. In this review we explore the potential for sex-specific differences in cardiac cachexia. We summarize advantages and disadvantages of clinical methods used to measure muscle mass and function and provide alternative measurements that should be considered in preclinical studies. Additionally, we summarize sex-dependent effects on muscle wasting in preclinical models of heart failure, disuse, and cancer. Lastly, we discuss the endocrine function of the heart and outline unanswered questions that could directly impact patient care.
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7
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Yedigaryan L, Gatti M, Marini V, Maraldi T, Sampaolesi M. Shared and Divergent Epigenetic Mechanisms in Cachexia and Sarcopenia. Cells 2022; 11:2293. [PMID: 35892590 PMCID: PMC9332174 DOI: 10.3390/cells11152293] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 01/27/2023] Open
Abstract
Significant loss of muscle mass may occur in cachexia and sarcopenia, which are major causes of mortality and disability. Cachexia represents a complex multi-organ syndrome associated with cancer and chronic diseases. It is often characterized by body weight loss, inflammation, and muscle and adipose wasting. Progressive muscle loss is also a hallmark of healthy aging, which is emerging worldwide as a main demographic trend. A great challenge for the health care systems is the age-related decline in functionality which threatens the independence and quality of life of elderly people. This biological decline can also be associated with functional muscle loss, known as sarcopenia. Previous studies have shown that microRNAs (miRNAs) play pivotal roles in the development and progression of muscle wasting in both cachexia and sarcopenia. These small non-coding RNAs, often carried in extracellular vesicles, inhibit translation by targeting messenger RNAs, therefore representing potent epigenetic modulators. The molecular mechanisms behind cachexia and sarcopenia, including the expression of specific miRNAs, share common and distinctive trends. The aim of the present review is to compile recent evidence about shared and divergent epigenetic mechanisms, particularly focusing on miRNAs, between cachexia and sarcopenia to understand a facet in the underlying muscle wasting associated with these morbidities and disclose potential therapeutic interventions.
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Affiliation(s)
- Laura Yedigaryan
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
| | - Martina Gatti
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (M.G.); (T.M.)
| | - Vittoria Marini
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
| | - Tullia Maraldi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (M.G.); (T.M.)
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (L.Y.); (V.M.)
- Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
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Identification of Potential miRNA-mRNA Regulatory Network in Denervated Muscular Atrophy by Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6042591. [PMID: 35800215 PMCID: PMC9256438 DOI: 10.1155/2022/6042591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022]
Abstract
Muscle atrophy caused by long-term denervation leads to the loss of skeletal muscle mass and strength, resulting in a poor recovery of functional muscles and decreasing quality of life. Increasing differentially expressed microRNAs (DEMs) have been reported to be involved in the pathogenesis of denervated muscle atrophy. However, there is still insufficient evidence to explain the role of miRNAs and their target genes in skeletal muscle atrophy. Therefore, an integrative exploration of the miRNA-mRNA regulatory network in denervated muscle atrophy is necessary. A total of 21 (16 upregulated and 5 downregulated) DEMs were screened out in the GSE81914 dataset. Med1, Myod1, Nfkb1, Rela, and Camta1 were predicted and verified to be significantly upregulated in denervated muscle atrophy, from which 6 key TF-miRNA relationship pairs, including Med1-mir-1949, Med1-mir-146b, Myod1-mir-29b, Nfkb1-mir-21, Rela-mir-21, and Camta1-mir-132, were obtained. 60 target genes were then predicted by submitting candidate DEMs to the miRNet database. GO and KEGG pathway enrichment analysis showed that target genes of DEMs were mainly enriched in the apoptotic process and PI3K/Akt signaling pathway. Through the PPI network construction, key modules and hub genes were obtained and potentially modulated by mir-29b, mir-132, and mir-133a. According to the qRT-PCR results, the expression of COL1A1 and Ctgf is opposite to their related miRNAs in denervated muscle atrophy. In the study, a potential miRNA-mRNA regulatory network was firstly constructed in denervated muscle atrophy, in which the mir-29b-COL1A1 and mir-133a-Ctgf pathways may provide new insights into the pathogenesis and treatment.
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Li J, Chen R, Zheng Y, Yuan W, Yang T, Zhu X, Yan Y, Jin B, Xu W, Zhang Z, Li G, Gokulnath P, Lei Z, Xiao J. Engineered Circular RNA CircmiR‐29b Attenuates Muscle Atrophy by Sponging MiR‐29b. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202200029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Jin Li
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Rui Chen
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Yongjun Zheng
- Division of Pain Management Huadong Hospital Affiliated to Fudan University Shanghai 200040 China
| | - Weilin Yuan
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Tingting Yang
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Xiaolan Zhu
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Yuwei Yan
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Bing Jin
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Wanru Xu
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Zhongrong Zhang
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
| | - Guoping Li
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA
| | - Priyanka Gokulnath
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School Boston MA 02114 USA
| | - Zhiyong Lei
- Department of Cardiology Laboratory of Experimental Cardiology University Medical Center Utrecht 3508GA Utrecht The Netherlands
| | - Junjie Xiao
- Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) School of Medicine Shanghai University Nantong 226011 China
- Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences Shanghai Engineering Research Center of Organ Repair School of Life Science Shanghai University Shanghai 200444 China
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Ishiguro T, Hayashi M, Fujiwara W, Okumura S, Yoshinaga M, Yamada R, Ueda S, Ito T, Niwa Y, Miyazaki A, Harada M, Naruse H, Ishii J, Ozaki Y, Izawa H. Circulating miR-489 as a potential new biomarker for idiopathic dilated cardiomyopathy. FUJITA MEDICAL JOURNAL 2022; 7:18-22. [PMID: 35111539 PMCID: PMC8749486 DOI: 10.20407/fmj.2020-001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/20/2020] [Indexed: 01/15/2023]
Abstract
Objectives:
MicroRNAs (miRNA) are functional RNAs that have emerged as pivotal gene expression
regulators in cardiac disease. Although several cardiomyocyte miRNAs have been reported to
play roles in heart failure progression among patients with idiopathic dilated cardiomyopathy
(DCM), the role of circulating miRNAs has not yet been well-examined. Methods:
After total RNA extraction from the peripheral blood samples of three control
participants and six patients with DCM, miRNA profiling was performed using miRNA arrays.
Based on the results of this initial screening, real-time polymerase chain reaction (RT-PCR)
was used to perform a quantitative analysis of blood samples from a larger number of matched
patients (DCM, n=20; controls, n=5). Finally, the
correlations between specific miRNA expression levels and hemodynamic parameters were
analyzed. Results:
A primary screening of 2,565 miRNAs resulted in the identification of nine miRNA
candidates. Quantitative RT-PCR results revealed significantly increased miR-489 expression
levels in the DCM group. Moreover, there was a significant positive correlation between
miR-489 expression level and left ventricular ejection fraction. Conclusions:
Our results suggest that circulating miR-489 could be a potential noninvasive
diagnostic biomarker for DCM. Additionally, the quantification of circulating miR-489 may have
value as a potential prognostic marker for patients with DCM.
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Affiliation(s)
- Tomoya Ishiguro
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Mutsuharu Hayashi
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Wakaya Fujiwara
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Satoshi Okumura
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Masataka Yoshinaga
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Ryo Yamada
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Sayano Ueda
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Takehiro Ito
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Yudai Niwa
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Akane Miyazaki
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Masahide Harada
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Hiroyuki Naruse
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Junnichi Ishii
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Hideo Izawa
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
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Park Y, Zhang Q, Fernandes JMO, Wiegertjes GF, Kiron V. Macrophage Heterogeneity in the Intestinal Cells of Salmon: Hints From Transcriptomic and Imaging Data. Front Immunol 2021; 12:798156. [PMID: 35003123 PMCID: PMC8733388 DOI: 10.3389/fimmu.2021.798156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/24/2021] [Indexed: 11/13/2022] Open
Abstract
The intestine has many types of cells that are present mostly in the epithelium and lamina propria. The importance of the intestinal cells for the mammalian mucosal immune system is well-established. However, there is no in-depth information about many of the intestinal cells in teleosts. In our previous study, we reported that adherent intestinal cells (AIC) predominantly express macrophage-related genes. To gather further evidence that AIC include macrophage-like cells, we compared their phagocytic activity and morphology with those of adherent head kidney cells (AKC), previously characterized as macrophage-like cells. We also compared equally abundant as well as differentially expressed mRNAs and miRNAs between AIC and AKC. AIC had lower phagocytic activity and were larger and more circular than macrophage-like AKC. RNA-Seq data revealed that there were 18309 mRNAs, with 59 miRNAs that were equally abundant between AIC and AKC. Integrative analysis of the mRNA and miRNA transcriptomes revealed macrophage heterogeneity in both AIC and AKC. In addition, analysis of AIC and AKC transcriptomes revealed functional characteristics of mucosal and systemic macrophages. Five pairs with significant negative correlations between miRNA and mRNAs were linked to macrophages and epithelial cells and their interaction could be pointing to macrophage activation and differentiation. The potential macrophage markers suggested in this study should be investigated under different immune conditions to understand the exact macrophage phenotypes.
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Affiliation(s)
- Youngjin Park
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Qirui Zhang
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | | | - Geert F. Wiegertjes
- Aquaculture and Fisheries Group, Wageningen University & Research, Wageningen, Netherlands
| | - Viswanath Kiron
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
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12
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Freire PP, Cury SS, Lopes LO, Fernandez GJ, Liu J, de Moraes LN, de Oliveira G, Oliveira JS, de Moraes D, Cabral-Marques O, Dal-Pai-Silva M, Hu X, Wang DZ, Carvalho RF. Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells. Cells 2021; 10:3527. [PMID: 34944037 PMCID: PMC8700610 DOI: 10.3390/cells10123527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/24/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
Interleukin-6 (IL-6) is a pro-inflammatory cytokine associated with skeletal muscle wasting in cancer cachexia. The control of gene expression by microRNAs (miRNAs) in muscle wasting involves the regulation of thousands of target transcripts. However, the miRNA-target networks associated with IL6-induced muscle atrophy remain to be characterized. Here, we show that IL-6 promotes the atrophy of C2C12 myotubes and changes the expression of 20 miRNAs (5 up-regulated and 15 down-regulated). Gene Ontology analysis of predicted miRNAs targets revealed post-transcriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Next, we performed a meta-analysis of miRNA-published data that identified miR-497-5p, a down-regulated miRNAs induced by IL-6, also down-regulated in other muscle-wasting conditions. We used miR-497-5p mimics and inhibitors to explore the function of miR-497-5p in C2C12 myoblasts and myotubes. We found that miR-497-5p can regulate the expression of the cell cycle genes CcnD2 and CcnE1 without affecting the rate of myoblast cellular proliferation. Notably, miR-497-5p mimics induced myotube atrophy and reduced Insr expression. Treatment with miR-497-5p inhibitors did not change the diameter of the myotubes but increased the expression of its target genes Insr and Igf1r. These genes are known to regulate skeletal muscle regeneration and hypertrophy via insulin-like growth factor pathway and were up-regulated in cachectic muscle samples. Our miRNA-regulated network analysis revealed a potential role for miR-497-5p during IL6-induced muscle cell atrophy and suggests that miR-497-5p is likely involved in a compensatory mechanism of muscle atrophy in response to IL-6.
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Affiliation(s)
- Paula P. Freire
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
| | - Sarah S. Cury
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Letícia O. Lopes
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Geysson J. Fernandez
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
- Faculty of Medicine, University of Antioquia, UdeA, Medellín 050010, Colombia
| | - Jianming Liu
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (J.L.); (X.H.); (D.-Z.W.)
| | - Leonardo Nazario de Moraes
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Grasieli de Oliveira
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Jakeline S. Oliveira
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Diogo de Moraes
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Otavio Cabral-Marques
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
- Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), São Paulo 05508-000, Brazil
| | - Maeli Dal-Pai-Silva
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
| | - Xiaoyun Hu
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (J.L.); (X.H.); (D.-Z.W.)
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (J.L.); (X.H.); (D.-Z.W.)
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Robson F. Carvalho
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu 18618-689, Brazil; (P.P.F.); (S.S.C.); (L.O.L.); (G.J.F.); (L.N.d.M.); (G.d.O.); (J.S.O.); (D.d.M.); (M.D.-P.-S.)
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13
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Sobieszek G, Mlak R, Powrózek T, Mazurek M, Skwarek-Dziekanowska A, Terlecki P, Małecka-Massalska T. Polymorphism of the ITGAM gene (rs7193943) and bioelectric impedance analysis as potential predictors of cachexia in chronic heart failure. Sci Rep 2021; 11:20145. [PMID: 34635743 PMCID: PMC8505625 DOI: 10.1038/s41598-021-99719-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/24/2021] [Indexed: 12/27/2022] Open
Abstract
Cardiac cachexia (CC) is an unfavorable metabolic syndrome leading to exacerbation of chronic heart failure (CHF) and a higher risk of death. The main factor contributing to the development of cachexia is the ongoing inflammatory process mediated by genes (e.g. Integrin Subunit Alpha M-ITGAM). The study aimed to assess the relationship between a single nucleotide polymorphism (SNP) -323G > A of the ITGAM and the occurrence of nutritional disorders in patients with CHF. 157 CHF patients underwent clinical and nutritional screening. Body composition was evaluated by bioelectrical impedance analysis (BIA). Patients with cachexia were characterized by significantly lower weight, body mass index (BMI), lower fat mass (FM), albumin, and hemoglobin. Lower values of BIA parameters: capacitance of membrane (Cm), phase angle (PA), and impedance ratio (Z200/Z5) were noted in women. Those patients demonstrated significantly higher values of creatinine, c-reactive protein (CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and pulmonary artery systolic pressure (PASP). A significantly higher risk of cachexia was reported in patients: aged ≥ 74 years (OR 3.55), with renal failure (OR 3.75), New York Heart Association classification (NYHA) III-IV (OR 2.83), with moderate or severe malnutrition according to the score of subjective global assessment (SGA) (OR 19.01) and AA genotype of ITGAM gene (OR 2.03). Determination of the -323G > A SNP in the ITGAM may prove to be a useful marker (after confirmation in further studies and appropriate validation) in the assessment of the risk of nutritional disorders in patients with CHF.
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Affiliation(s)
- Grzegorz Sobieszek
- Department of Cardiology, 1St Military Clinical Hospital with the Outpatient Clinic, al. Racławickie 23, 20-048, Lublin, Poland.
| | - Radosław Mlak
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland.
| | - Tomasz Powrózek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Marcin Mazurek
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Aneta Skwarek-Dziekanowska
- Department of Cardiology, 1St Military Clinical Hospital with the Outpatient Clinic, al. Racławickie 23, 20-048, Lublin, Poland
| | - Piotr Terlecki
- Department of Vascular Surgery and Angiology, Medical University of Lublin, Lublin, Poland
| | - Teresa Małecka-Massalska
- Department of Human Physiology, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland
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14
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miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis. Int J Mol Sci 2021; 22:ijms221910574. [PMID: 34638915 PMCID: PMC8509017 DOI: 10.3390/ijms221910574] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 12/21/2022] Open
Abstract
Pulmonary artery hypertension (PAH) pathology involves extracellular matrix (ECM) remodeling in cardiac tissues, thus promoting cardiac fibrosis progression. miR-29a-3p reportedly inhibits lung progression and liver fibrosis by regulating ECM protein expression; however, its role in PAH-induced fibrosis remains unclear. In this study, we aimed to investigate the role of miR-29a-3p in cardiac fibrosis progression in PAH and its influence on ECM protein thrombospondin-2 (THBS2) expression. The diagnostic and prognostic values of miR-29a-3p and THBS2 in PAH were evaluated. The expressions and effects of miR-29a-3p and THBS2 were assessed in cell culture, monocrotaline-induced PAH mouse model, and patients with PAH. The levels of circulating miR-29a-3p and THBS2 in patients and mice with PAH decreased and increased, respectively. miR-29a-3p directly targets THBS2 and regulates THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis. The circulating levels of miR-29a-3p and THBS2 were correlated with PAH diagnostic parameters, suggesting their independent prognostic value. miR-29a-3p targeted THBS2 expression via a direct anti-fibrotic effect on PAH-induced cardiac fibrosis, indicating miR-29a-3p acts as a messenger with promising therapeutic effects.
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15
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Zhuo X, Bai K, Wang Y, Liu P, Xi W, She J, Liu J. Long-chain noncoding RNA-GAS5/hsa-miR-138-5p attenuates high glucose-induced cardiomyocyte damage by targeting CYP11B2. Biosci Rep 2021; 41:BSR20202232. [PMID: 33682891 PMCID: PMC8485392 DOI: 10.1042/bsr20202232] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/16/2020] [Accepted: 11/24/2020] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Diabetic cardiomyopathy (DCM) is one of the complications experienced by patients with diabetes. In recent years, long noncoding RNAs (lncRNAs) have been investigated because of their role in the progression of various diseases, including DCM. The purpose of the present study was to explore the role of lncRNA GAS5 in high glucose (HG)-induced cardiomyocyte injury and apoptosis. MATERIALS AND METHODS We constructed HG-induced AC16 cardiomyocytes and a streptozotocin (STZ)-induced rat diabetes model. GAS5 was overexpressed and knocked out at the cellular level, and GAS5 was knocked down by lentiviruses at the animal level to observe its effect on myocardial injury. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of GAS5. Cell proliferation and apoptosis after GAS5 knockout were detected by CCK-8, TUNEL, and flow cytometry assays. ELISA was used to detect the changes in myocardial enzyme content in cells and animal myocardial tissues during the action of GAS5 on myocardial injury. RESULTS GAS5 expression was up-regulated in HG-treated AC16 cardiomyocytes and the rat diabetic myocardial injury model. The down-regulation of GAS5 could inhibit HG-induced myocardial damage. This work proved that the down-regulation of GAS5 could reverse cardiomyocyte injury and apoptosis by targeting miR-138 to down-regulate CYP11B2. CONCLUSION We confirmed for the first time that the down-regulation of GAS5 could reverse CYP11B2 via the miR-138 axis to reverse HG-induced cardiomyocyte injury. This research might provide a new direction for explaining the developmental mechanism of DCM and potential targets for the treatment of myocardial injury.
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Affiliation(s)
- Xiaozhen Zhuo
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Kai Bai
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Yingxian Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Peining Liu
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Wen Xi
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Jianqing She
- Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
| | - Junhui Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
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16
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Mariano TB, de Souza Castilho AC, de Almeida Sabela AKD, de Oliveira AC, Cury SS, Aguiar AF, Dias RDJD, Cicogna AC, Okoshi K, Junior LAJ, Carvalho RF, Pacagnelli FL. Preventive training does not interfere with mRNA-encoding myosin and collagen expression during pulmonary arterial hypertension. PLoS One 2021; 16:e0244768. [PMID: 34495964 PMCID: PMC8425576 DOI: 10.1371/journal.pone.0244768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 08/17/2021] [Indexed: 11/22/2022] Open
Abstract
To gain insight on the impact of preventive exercise during pulmonary arterial hypertension (PAH), we evaluated the gene expression of myosins and gene-encoding proteins associated with the extracellular matrix remodeling of right hypertrophied ventricles. We used 32 male Wistar rats, separated in four groups: Sedentary Control (S, n = 8); Control with Training (T, n = 8); Sedentary with Pulmonary Arterial Hypertension (SPAH, n = 8); and Pulmonary Arterial Hypertension with Training (TPAH, n = 8). All rats underwent a two-week adaptation period; T and TPAH group rats then proceeded to an eight-week training period on a treadmill. At the beginning of the 11th week, S and T groups received an intraperitoneal injection of saline, and SPAH and TPAH groups received an injection of monocrotaline (60 mg/kg). Rats in the T and TPAH groups then continued with the training protocol until the 13th week. We assessed exercise capacity, echocardiography analysis, Fulton's index, cross-sectional areas of cardiomyocytes, collagen content and types, and fractal dimension (FD). Transcript abundance of myosins and extracellular matrix genes were estimated through reverse transcription-quantitative PCR (RT-qPCR). When compared to the SPAH group, the TPAH group showed increases in functional capacity and pulmonary artery acceleration time/pulmonary ejection time ratio and decreases in Fulton's index and cross-sectional areas of myocyte cells. However, preventive exercise did not induce alterations in col1a1 and myh7 gene expression. Our findings demonstrate that preventive exercise improved functional capacity, reduced cardiac hypertrophy, and attenuated PH development without interfering in mRNA-encoding myosin and collagen expression during PAH.
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MESH Headings
- Animals
- Male
- Rats, Wistar
- Physical Conditioning, Animal
- Rats
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Collagen/metabolism
- Collagen/genetics
- Pulmonary Arterial Hypertension/genetics
- Pulmonary Arterial Hypertension/metabolism
- Myosins/metabolism
- Myosins/genetics
- Hypertension, Pulmonary/genetics
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/prevention & control
- Monocrotaline
- Gene Expression Regulation
- Hypertrophy, Right Ventricular/genetics
- Hypertrophy, Right Ventricular/metabolism
- Hypertrophy, Right Ventricular/prevention & control
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Affiliation(s)
- Thaoan Bruno Mariano
- Postgraduate Program in Animal Science, University of Western São Paulo (UNOESTE), Presidente Prudente, São Paulo, Brazil
| | | | | | - André Casanova de Oliveira
- Postgraduate Program in Animal Science, University of Western São Paulo (UNOESTE), Presidente Prudente, São Paulo, Brazil
| | - Sarah Santiloni Cury
- Department of Structural and Functional Biology, Institute of Biosciences, UNESP, Botucatu, São Paulo, Brazil
| | - Andreo Fernando Aguiar
- Postgraduate Program in Physical Exercise in Health Promotion, Northern University of Paraná, Londrina, Paraná, Brazil
| | - Raisa de Jesus Dutra Dias
- Department of Physiotherapy, University of Western São Paulo (UNOESTE), Presidente Prudente, São Paulo, Brazil
| | - Antonio Carlos Cicogna
- Department of Internal Medicine, Botucatu Medical School, UNESP, Botucatu, São Paulo, Brazil
| | - Katashi Okoshi
- Department of Internal Medicine, Botucatu Medical School, UNESP, Botucatu, São Paulo, Brazil
| | | | - Robson Francisco Carvalho
- Department of Structural and Functional Biology, Institute of Biosciences, UNESP, Botucatu, São Paulo, Brazil
| | - Francis Lopes Pacagnelli
- Postgraduate Program in Animal Science, University of Western São Paulo (UNOESTE), Presidente Prudente, São Paulo, Brazil
- Department of Physiotherapy, University of Western São Paulo (UNOESTE), Presidente Prudente, São Paulo, Brazil
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17
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Belli R, Ferraro E, Molfino A, Carletti R, Tambaro F, Costelli P, Muscaritoli M. Liquid Biopsy for Cancer Cachexia: Focus on Muscle-Derived microRNAs. Int J Mol Sci 2021; 22:ijms22169007. [PMID: 34445710 PMCID: PMC8396502 DOI: 10.3390/ijms22169007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer cachexia displays a complex nature in which systemic inflammation, impaired energy metabolism, loss of muscle and adipose tissues result in unintentional body weight loss. Cachectic patients have a poor prognosis and the presence of cachexia reduces the tolerability of chemo/radio-therapy treatments and it is frequently the primary cause of death in advanced cancer patients. Early detection of this condition could make treatments more effective. However, early diagnostic biomarkers of cachexia are currently lacking. In recent years, although solid biopsy still remains the "gold standard" for diagnosis of cancer, liquid biopsy is gaining increasing interest as a source of easily accessible potential biomarkers. Moreover, the growing interest in circulating microRNAs (miRNAs), has made these molecules attractive for the diagnosis of several diseases, including cancer. Some muscle-derived circulating miRNA might play a pivotal role in the onset/progression of cancer cachexia. This topic is of great interest since circulating miRNAs might be easily detectable by means of liquid biopsies and might allow an early diagnosis of this syndrome. We here summarize the current knowledge on circulating muscular miRNAs involved in muscle atrophy, since they might represent easily accessible and promising biomarkers of cachexia.
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Affiliation(s)
- Roberta Belli
- Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; (A.M.); (R.C.); (F.T.)
- Correspondence: (R.B.); (M.M.); Tel./Fax: +390-649-972-020 (M.M.)
| | - Elisabetta Ferraro
- Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56126 Pisa, Italy;
| | - Alessio Molfino
- Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; (A.M.); (R.C.); (F.T.)
| | - Raffaella Carletti
- Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; (A.M.); (R.C.); (F.T.)
| | - Federica Tambaro
- Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; (A.M.); (R.C.); (F.T.)
| | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Torino, 10124 Torino, Italy;
| | - Maurizio Muscaritoli
- Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy; (A.M.); (R.C.); (F.T.)
- Correspondence: (R.B.); (M.M.); Tel./Fax: +390-649-972-020 (M.M.)
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18
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Liu C, Li L, Ge M, Gu L, Zhang K, Su Y, Zhang Y, Liu C, Lan M, Yu Y, Wang T, Zhang B, Zhou G, Meng Q. MiR-29ab1 Cluster Resists Muscle Atrophy Through Inhibiting MuRF1. DNA Cell Biol 2021; 40:1167-1176. [PMID: 34255539 DOI: 10.1089/dna.2021.0267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Skeletal muscle has great plasticity. An increase in protein degradation can cause muscle atrophy. Atrogin-1 and muscle ring finger-1 (MuRF1) are dramatically upregulated in various muscle atrophy. Inhibition of Atrogin-1 and MuRF1 protects against muscle atrophy. MiR-29 plays an important regulatory role in skeletal muscle development. However, the function of miR-29 in skeletal muscle protein metabolism is not clear. To investigate the function of miR-29, we generated miR-29 knockout mice and the miR-29ab1 cluster overexpression mice. The disruption of miR-29 led to severe atrophy of skeletal muscle during puberty, and the muscle-specific overexpression of the miR-29ab1 cluster protected against denervation-induced and fasting-induced muscle atrophy. Furthermore, the overexpression of miR-29a, b mimics in myotubes resisted the muscle atrophy. MuRF1 was the direct target gene of miR-29a, b. These results demonstrate that miR-29ab1 cluster plays a critical role in the maintenance of skeletal muscle. MiR-29ab1 cluster is the excellent inhibitor of MuRF1, ultimately indicating that miR-29ab1 cluster is good therapeutic molecule candidate for adulthood.
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Affiliation(s)
- Chuncheng Liu
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, China
| | - Lei Li
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Mengxu Ge
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Lijie Gu
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Kuo Zhang
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yang Su
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yuying Zhang
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Chang Liu
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Miaomiao Lan
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yingying Yu
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Tongtong Wang
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Bing Zhang
- Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, China Agricultural University, Beijing, China
| | - Guangbin Zhou
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
| | - Qingyong Meng
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Science, China Agricultural University, Beijing, China
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Rabajdova M, Spakova I, Zelko A, Rosenberger J, Kolarcik P, Sobolova V, Pella D, Marekova M, Madarasova Geckova A. The role of physical activity and miRNAs in the vascular aging and cardiac health of dialysis patients. Physiol Rep 2021; 9:e14879. [PMID: 34042291 PMCID: PMC8157788 DOI: 10.14814/phy2.14879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/19/2022] Open
Abstract
Cardiovascular comorbidities are independent risk factors for mortality in dialysis patients. MicroRNA signaling has an important role in vascular aging and cardiac health, while physical activity is a primary nonpharmacologic treatment for cardiovascular comorbidities in dialysis patients. To identify the relationships between muscle function, miRNA signaling pathways, the presence of vascular calcifications and the severity of cardiovascular comorbidities, we initially enrolled 90 subjects on hemodialysis therapy and collected complete data from 46 subjects. A group of 26 subjects inactiv group (INC) was monitored during 12 weeks of physical inactivity and another group of 20 patients exercise group (EXC) was followed during 12 weeks of intradialytic, moderate intensity, resistance training intervention applied three times per week. In both groups, we assessed the expression levels of myo‐miRNAs, proteins, and muscle function (MF) before and after the 12‐week period. Data on the presence of vascular calcifications and the severity of cardiac comorbidities were collected from the patients’ EuCliD® records. Using a full structural equitation modelling of the total study sample, we found that the higher the increase in MF was observed in patients, the higher the probability of a decrease in the expression of miR‐206 and TRIM63 and the lower severity of cardiac comorbidities. A reduced structural model in INC patients showed that the higher the decrease in MF, the higher the probability of the presence of calcifications and the higher severity of cardiac comorbidities. In EXC patients, we found that the higher the increase in MF, the lower the probability of higher severity of cardiovascular comorbidities.
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Affiliation(s)
- Miroslava Rabajdova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Ivana Spakova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Aurel Zelko
- Department of Health Psychology and Research Methodology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.,Graduate School Kosice Institute for Society and Health, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Jaroslav Rosenberger
- Department of Health Psychology and Research Methodology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.,Graduate School Kosice Institute for Society and Health, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.,2nd Department of Internal Medicine, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.,Fresenius Medical Care - Dialysis Services Kosice, Kosice, Slovakia.,Olomouc University Social Health Institute, Palacky University, Olomouc, Czech Republic
| | - Peter Kolarcik
- Department of Health Psychology and Research Methodology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Vladimira Sobolova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Daniel Pella
- 2nd Department of Cardiology, Faculty of Medicine, Pavol Jozef Safarik University and East Slovak Institute of Cardiovascular Diseases, Kosice, Slovakia
| | - Maria Marekova
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Andrea Madarasova Geckova
- Department of Health Psychology and Research Methodology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.,Olomouc University Social Health Institute, Palacky University, Olomouc, Czech Republic
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20
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Wang R, Peng L, Lv D, Shang F, Yan J, Li G, Li D, Ouyang J, Yang J. Leonurine Attenuates Myocardial Fibrosis Through Upregulation of miR-29a-3p in Mice Post-myocardial Infarction. J Cardiovasc Pharmacol 2021; 77:189-199. [PMID: 33235025 DOI: 10.1097/fjc.0000000000000957] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/31/2020] [Indexed: 01/06/2023]
Abstract
ABSTRACT Myocardial fibrosis (MF) is a pathological process that accelerates cardiac remodeling in myocardial infarction (MI), and miR-29 has become one of the foci of research into MF. As an alkaloid extracted from Herba leonuri, leonurine (LE) has been found to be an effective natural active ingredient for inhibiting fibrosis in many preclinical experiments. However, whether LE protects against MF after MI through modifying miR-29 remains unclear. The present study aimed to investigate the therapeutic effects of LE on MF, and to elucidate the underlying mechanisms involved. A mouse model of MI was established, followed by administration of LE for 4 weeks. We found that LE effectively improved cardiac function, and attenuated fibrosis and cardiac remodeling in mice post-MI. In vitro, LE simultaneously inhibited proliferation and migration of neonatal mouse cardiac fibroblasts (CFs) exposed to angiotensin II (Ang II), and the activation of collagen synthesis and myofibroblast generation was markedly suppressed by LE. Notably, we found that all mature miR-29 family members were downregulated in the myocardial tissues of mice post-MI, whereas LE significantly upregulated miR-29a-3p expression, and such upregulation was also detected in LE-treated CFs under Ang II stimulation. Knockdown of miR-29a-3p by a specific miRNA inhibitor upregulated the protein levels of TGF-β, collagen III, and collagen I in CFs, and completely reversed the antifibrotic effects of LE on CFs. Our study suggests that LE exerts cardioprotective effects against MF, possibly through the upregulation of miR-29a-3p.
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Affiliation(s)
- Ruiyu Wang
- Department of Cardiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Linqian Peng
- Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Dingyi Lv
- Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Feifei Shang
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Jianghong Yan
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Guoxing Li
- Department of Cardiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dan Li
- Department of Cardiology, the People's Hospital of Bishan District, Chongqing, China
| | - Jing Ouyang
- Department of Pharmacy, Chongqing Public Health Medical Center, Chongqing, China; and
| | - Jiadan Yang
- Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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21
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Deciphering the miRNA transcriptome of breast muscle from the embryonic to post-hatching periods in chickens. BMC Genomics 2021; 22:64. [PMID: 33468053 PMCID: PMC7816426 DOI: 10.1186/s12864-021-07374-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 01/07/2021] [Indexed: 12/02/2022] Open
Abstract
Background miRNAs play critical roles in growth and development. Various studies of chicken muscle development have focused on identifying miRNAs that are important for embryo or adult muscle development. However, little is known about the role of miRNAs in the whole muscle development process from embryonic to post-hatching periods. Here, we present a comprehensive investigation of miRNA transcriptomes at 12-day embryo (E12), E17, and day 1 (D1), D14, D56 and D98 post-hatching stages. Results We identified 337 differentially expressed miRNAs (DE-miRNAs) during muscle development. A Short Time-Series Expression Miner analysis identified two significantly different expression profiles. Profile 4 with downregulated pattern contained 106 DE-miRNAs, while profile 21 with upregulated pattern contained 44 DE-miRNAs. The DE-miRNAs with the upregulated pattern mainly played regulatory roles in cellular turnover, such as pyrimidine metabolism, DNA replication, and cell cycle, whereas DE-miRNAs with the downregulated pattern directly or indirectly contributed to protein turnover metabolism such as glycolysis/gluconeogenesis, pyruvate metabolism and biosynthesis of amino acids. Conclusions The main functional miRNAs during chicken muscle development differ between embryonic and post-hatching stages. miRNAs with an upregulated pattern were mainly involved in cellular turnover, while miRNAs with a downregulated pattern mainly played a regulatory role in protein turnover metabolism. These findings enrich information about the regulatory mechanisms involved in muscle development at the miRNA expression level, and provide several candidates for future studies concerning miRNA-target function in regulation of chicken muscle development. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07374-y.
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22
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Li J, Yang T, Sha Z, Tang H, Hua X, Wang L, Wang Z, Gao Z, Sluijter JPG, Rowe GC, Das S, Yang L, Xiao J. Angiotensin II-induced muscle atrophy via PPARγ suppression is mediated by miR-29b. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 23:743-756. [PMID: 33614226 PMCID: PMC7868689 DOI: 10.1016/j.omtn.2020.12.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 12/19/2020] [Indexed: 12/20/2022]
Abstract
The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both in vitro and in vivo. IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.
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Affiliation(s)
- Jin Li
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Tingting Yang
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Zhao Sha
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Haifei Tang
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Xuejiao Hua
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Lijun Wang
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Zitong Wang
- Department of Pathophysiology, Basic Medical Science, Harbin Medical University, Harbin 150081, China
| | - Ziyu Gao
- Department of Pathophysiology, Basic Medical Science, Harbin Medical University, Harbin 150081, China
| | - Joost P G Sluijter
- Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht 3508GA, the Netherlands.,UMC Utrecht Regenerative Medicine Center, University Medical Center, Utrecht University, Utrecht 3508GA, the Netherlands
| | - Glenn C Rowe
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Saumya Das
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215, USA
| | - Liming Yang
- Department of Pathophysiology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Junjie Xiao
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
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23
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Choi SA, Koh EJ, Kim RN, Byun JW, Phi JH, Yang J, Wang KC, Park AK, Hwang DW, Lee JY, Kim SK. Extracellular vesicle-associated miR-135b and -135a regulate stemness in Group 4 medulloblastoma cells by targeting angiomotin-like 2. Cancer Cell Int 2020; 20:558. [PMID: 33292274 PMCID: PMC7678136 DOI: 10.1186/s12935-020-01645-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/09/2020] [Indexed: 12/18/2022] Open
Abstract
Background Extracellular vesicles (EVs) secreted by tumours, including exosomes, are important factors that regulate cell–cell interactions in oncogenesis. Although EV studies are ongoing, the biological understanding of EV-miRNAs derived from brain tumour spheroid-forming cells (BTSCs) of medulloblastoma is poor. Purposes We explored the specific cellular miRNAs and EV-miRNAs in medulloblastoma BTSCs to determine their potential biological function. Methods Bulk tumor cells (BTCs) and BTSCs were cultured under different conditions from medulloblastoma tissues (N = 10). Results Twenty-four miRNAs were simultaneously increased in both cells and EVs derived from BTSCs in comparison to BTCs. After inhibition of miR-135b or miR135a which were the most significantly increased in BTSCs, cell viability, self-renewal and stem cell marker expression decreased remarkably. Through integrated analysis of mRNAs and miRNAs data, we found that angiomotin-like 2 (AMOTL2), which was significantly decreased, was targeted by both miR-135b and miR-135a. STAT6 and GPX8 were targeted only by miR-135a. Importantly, low expression of AMOTL2 was significantly associated with overall poor survival in paediatric Group 3 and Group 4 medulloblastoma patients. Conclusion Our results indicated that inhibition of miR-135b or miR-135a leads to suppress stemness of BTSC through modulation of AMOTL2.
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Affiliation(s)
- Seung Ah Choi
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Jung Koh
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Regional Emergency Medical Center, Seoul National University Hospital, Seoul, Korea
| | - Ryong Nam Kim
- Department of Biomedical Engineering, Seoul National University, Seoul, Korea
| | - Jung Woo Byun
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hoon Phi
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jeyul Yang
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Kyu-Chang Wang
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Ae Kyung Park
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Korea
| | - Do Won Hwang
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Yeoun Lee
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.,Department of Anatomy, Neural Development and Anomaly Lab, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Ki Kim
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. .,Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
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24
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Liu Q, Gao J, Deng J, Xiao J. Current Studies and Future Directions of Exercise Therapy for Muscle Atrophy Induced by Heart Failure. Front Cardiovasc Med 2020; 7:593429. [PMID: 33195482 PMCID: PMC7644508 DOI: 10.3389/fcvm.2020.593429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/01/2020] [Indexed: 12/12/2022] Open
Abstract
Muscle atrophy is a common complication of heart failure. At present, there is no specific treatment to reverse the course of muscle atrophy. Exercise training, due to the safety and easy operation, is a recommended therapy for muscle atrophy induced by heart failure. However, the patients with muscle atrophy are weak in mobility and may not be able to train for a long time. Therefore, it is necessary to explore novel targets of exercise protection for muscle atrophy, so as to improve the quality of life and survival rate of patients with muscular atrophy induced by heart failure. This article aims to review latest studies, summarize the evidence and limitations, and provide a glimpse into the future of exercise for the treatment of muscle atrophy induced by heart failure. We wish to highlight some important findings about the essential roles of exercise sensors in muscle atrophy induced by heart failure, which might be helpful for searching potential therapeutic targets for muscle wasting induced by heart failure.
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Affiliation(s)
- Qi Liu
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Juan Gao
- School of Medicine, Shanghai University, Shanghai, China
| | - Jiali Deng
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China
| | - Junjie Xiao
- Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China.,School of Medicine, Shanghai University, Shanghai, China
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25
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Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus-One of Several Possible Reasons for an Increased Cardiovascular Risk. Cells 2020; 9:cells9061557. [PMID: 32604801 PMCID: PMC7349356 DOI: 10.3390/cells9061557] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/19/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3-11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
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26
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Fernandez GJ, Ferreira JH, Vechetti IJ, de Moraes LN, Cury SS, Freire PP, Gutiérrez J, Ferretti R, Dal-Pai-Silva M, Rogatto SR, Carvalho RF. MicroRNA-mRNA Co-sequencing Identifies Transcriptional and Post-transcriptional Regulatory Networks Underlying Muscle Wasting in Cancer Cachexia. Front Genet 2020; 11:541. [PMID: 32547603 PMCID: PMC7272700 DOI: 10.3389/fgene.2020.00541] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/05/2020] [Indexed: 12/23/2022] Open
Abstract
Cancer cachexia is a metabolic syndrome with alterations in gene regulatory networks that consequently lead to skeletal muscle wasting. Integrating microRNAs-mRNAs omics profiles offers an opportunity to understand transcriptional and post-transcriptional regulatory networks underlying muscle wasting. Here, we used RNA sequencing to simultaneously integrate and explore microRNAs and mRNAs expression profiles in the tibialis anterior (TA) muscles of the Lewis Lung Carcinoma (LLC) model of cancer cachexia. We found 1,008 mRNAs and 18 microRNAs differentially expressed in cachectic mice compared with controls. Although our transcriptomic analysis demonstrated a high heterogeneity in mRNA profiles of cachectic mice, we identified a reduced number of differentially expressed genes that were uniformly regulated within cachectic muscles. This set of uniformly regulated genes is associated with the extracellular matrix (ECM), proteolysis, and inflammatory response. We also used transcriptomic data to perform enrichment analysis of transcriptional factor binding sites in promoter sequences, which revealed activation of the atrophy-related transcription factors NF-κB, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and microRNA expression profiles identified post-transcriptional regulation by microRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and the FoxO signaling pathway. Our integrative analysis of microRNA-mRNA co-profiles comprehensively characterized regulatory relationships of molecular pathways and revealed microRNAs targeting ECM-associated genes in cancer cachexia.
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Affiliation(s)
- Geysson Javier Fernandez
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil.,Faculty of Medicine, University of Antioquia, Medellín, Colombia
| | - Juarez Henrique Ferreira
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Ivan José Vechetti
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Leonardo Nazario de Moraes
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Sarah Santiloni Cury
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Paula Paccielli Freire
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Jayson Gutiérrez
- Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium
| | - Renato Ferretti
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Maeli Dal-Pai-Silva
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
| | - Silvia Regina Rogatto
- Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle, Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Robson Francisco Carvalho
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, Brazil
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27
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Chu L, Yu L, Liu J, Song S, Yang H, Han F, Liu F, Hu Y. Long intergenic non-coding LINC00657 regulates tumorigenesis of glioblastoma by acting as a molecular sponge of miR-190a-3p. Aging (Albany NY) 2020; 11:1456-1470. [PMID: 30837348 PMCID: PMC6428093 DOI: 10.18632/aging.101845] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 02/22/2019] [Indexed: 12/14/2022]
Abstract
To detect the aberrantly expressed long non-coding RNAs in glioblastoma, two pairs of glioblastoma and adjacent normal tissues were firstly analyzed by RNA sequencing. Long intergenic non-coding RNA LINC00657 was considered to play a vital role in glioblastoma based on the results of RNA sequencing. Hence, we aimed to investigate the mechanisms by which LINC00657 regulated the tumorigenesis of glioblastoma. The level of LINC00657 in 40 glioblastoma samples and glioblastoma cell lines was detected by RT-qPCR. LINC00657 was significantly decreased in patients with glioblastoma compared with adjacent normal tissues. Overexpression of LINC00657 inhibited proliferation, colony formation, invasion and migration in glioma cells via inducing apoptosis. Dual luciferase report assay indicated LINC00657 was the target of miR-190a-3p. Overexpression of LINC00657 greatly inhibited the relative amount of miR-190a-3p. Besides, miR-190a-3p was found to be a negative regulator of PTEN. Additionally, active-caspase 3 was increased in cells transfected with pcDNA3.1-LINC00657. Finally, in vitro results were further confirmed by in vivo studies using nude mice bearing with glioblastoma tumors. In conclusion, LINC00657 was effective in inhibiting glioblastoma by acting as a molecular sponge of miR-190a-3p to regulate PTEN expression. Therefore, targeting LINC00657 may serve as a potential strategy for the treatment of patients with glioblastoma.
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Affiliation(s)
- Liangzhao Chu
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Lei Yu
- Prenatal Diagnosis Center, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Jian Liu
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Shibin Song
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Hua Yang
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Feng Han
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Fen Liu
- Department of Neurosurgery, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Yaxin Hu
- Prenatal Diagnosis Center, Hospital affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China
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28
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The Emerging Role of MicroRNAs and Other Non-Coding RNAs in Cancer Cachexia. Cancers (Basel) 2020; 12:cancers12041004. [PMID: 32325796 PMCID: PMC7226600 DOI: 10.3390/cancers12041004] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer cachexia or wasting is a paraneoplastic syndrome characterized by systemic inflammation and an involuntary loss of body mass that cannot be reversed by normal nutritional support. This syndrome affects 50%–80% of cancer patients, depending on the tumor type and patient characteristics, and it is responsible for up to 20% of cancer deaths. MicroRNAs are a class of non-coding RNAs (ncRNAs) with 19 to 24 nucleotides in length of which the function is to regulate gene expression. In the last years, microRNAs and other ncRNAs have been demonstrated to have a crucial role in the pathogenesis of several diseases and clinical potential. Recently, ncRNAs have begun to be associated with cancer cachexia by modulating essential functions like the turnover of skeletal muscle and adipose tissue. Additionally, circulating microRNAs have been suggested as potential biomarkers for patients at risk of developing cancer cachexia. In this review article, we present recent data concerning the role of microRNAs and other ncRNAs in cancer cachexia pathogenesis and their possible clinical relevance.
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Diabetes Mellitus and Cardiovascular Risk Assessment in Mothers with a History of Gestational Diabetes Mellitus Based on Postpartal Expression Profile of MicroRNAs Associated with Diabetes Mellitus and Cardiovascular and Cerebrovascular Diseases. Int J Mol Sci 2020; 21:ijms21072437. [PMID: 32244558 PMCID: PMC7177375 DOI: 10.3390/ijms21072437] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Mothers with a history of gestational diabetes mellitus (GDM) have an increased risk of developing diabetes in the future and a lifelong cardiovascular risk. Postpartal expression profile of cardiovascular/cerebrovascular disease associated microRNAs was assessed 3–11 years after the delivery in whole peripheral blood of young and middle-aged mothers with a prior exposure to GDM with the aim to identify a high-risk group of mothers at risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases who would benefit from implementation of early primary prevention strategies and long-term follow-up. The hypothesis of the assessment of cardiovascular risk in women was based on the knowledge that a series of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases. Abnormal expression profile of multiple microRNAs was found in women with a prior exposure to GDM (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-100-5p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, miR-342-3p, miR-499a-5p, and-miR-574-3p). Postpartal combined screening of miR-1-3p, miR-16-5p, miR-17-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p showed the highest accuracy for the identification of mothers with a prior exposure to GDM at a higher risk of later development of cardiovascular/cerebrovascular diseases (AUC 0.900, p < 0.001, sensitivity 77.48%, specificity 93.26%, cut off >0.611270413). It was able to identify 77.48% mothers with an increased cardiovascular risk at 10.0% FPR. Any of changes in epigenome (upregulation of miR-16-5p, miR-17-5p, miR-29a-3p, and miR-195-5p) that were induced by GDM-complicated pregnancy are long-acting and may predispose mothers affected with GDM to later development of diabetes mellitus and cardiovascular/cerebrovascular diseases. In addition, novel epigenetic changes (upregulation of serious of microRNAs) appeared in a proportion of women that were exposed to GDM throughout the postpartal life. Likewise, a previous occurrence of either GH, PE, and/or FGR, as well as a previous occurrence of GDM, is associated with the upregulation of miR-1-3p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-199a-5p, miR-221-3p, and miR-499a-5p. On the other hand, upregulation of miR-16-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-103a-3p, miR-195-5p, miR-342-3p, and miR-574-3p represents a unique feature of aberrant expression profile of women with a prior exposure to GDM. Screening of particular microRNAs may stratify a high-risk group of mothers with a history of GDM who might benefit from implementation of early primary prevention strategies.
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Bonnet S, Boucherat O, Paulin R, Wu D, Hindmarch CCT, Archer SL, Song R, Moore JB, Provencher S, Zhang L, Uchida S. Clinical value of non-coding RNAs in cardiovascular, pulmonary, and muscle diseases. Am J Physiol Cell Physiol 2019; 318:C1-C28. [PMID: 31483703 DOI: 10.1152/ajpcell.00078.2019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although a majority of the mammalian genome is transcribed to RNA, mounting evidence indicates that only a minor proportion of these transcriptional products are actually translated into proteins. Since the discovery of the first non-coding RNA (ncRNA) in the 1980s, the field has gone on to recognize ncRNAs as important molecular regulators of RNA activity and protein function, knowledge of which has stimulated the expansion of a scientific field that quests to understand the role of ncRNAs in cellular physiology, tissue homeostasis, and human disease. Although our knowledge of these molecules has significantly improved over the years, we have limited understanding of their precise functions, protein interacting partners, and tissue-specific activities. Adding to this complexity, it remains unknown exactly how many ncRNAs there are in existence. The increased use of high-throughput transcriptomics techniques has rapidly expanded the list of ncRNAs, which now includes classical ncRNAs (e.g., ribosomal RNAs and transfer RNAs), microRNAs, and long ncRNAs. In addition, splicing by-products of protein-coding genes and ncRNAs, so-called circular RNAs, are now being investigated. Because there is substantial heterogeneity in the functions of ncRNAs, we have summarized the present state of knowledge regarding the functions of ncRNAs in heart, lungs, and skeletal muscle. This review highlights the pathophysiologic relevance of these ncRNAs in the context of human cardiovascular, pulmonary, and muscle diseases.
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Affiliation(s)
- Sébastien Bonnet
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada.,Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Olivier Boucherat
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada.,Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Roxane Paulin
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada.,Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Danchen Wu
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Charles C T Hindmarch
- Queen's Cardiopulmonary Unit, Translational Institute of Medicine, Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Stephen L Archer
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Rui Song
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Joseph B Moore
- Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.,The Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Steeve Provencher
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada.,Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California
| | - Shizuka Uchida
- Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky.,The Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, Kentucky.,Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky
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Freire PP, Fernandez GJ, Cury SS, de Moraes D, Oliveira JS, de Oliveira G, Dal-Pai-Silva M, Dos Reis PP, Carvalho RF. The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis. Int J Mol Sci 2019; 20:E1962. [PMID: 31013615 PMCID: PMC6515458 DOI: 10.3390/ijms20081962] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/05/2019] [Accepted: 04/11/2019] [Indexed: 12/15/2022] Open
Abstract
Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%-80% of cancer patients, depending on the tumor type, and is associated with 20%-40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy-a key feature in cancer cachexia-no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA-mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA-mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies.
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Affiliation(s)
- Paula Paccielli Freire
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Geysson Javier Fernandez
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Sarah Santiloni Cury
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Diogo de Moraes
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Jakeline Santos Oliveira
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Grasieli de Oliveira
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Maeli Dal-Pai-Silva
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
| | - Patrícia Pintor Dos Reis
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-687, Brazil.
- Experimental Research Unity, Faculty of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-687, Brazil.
| | - Robson Francisco Carvalho
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo 18.618-619, Brazil.
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Hromadnikova I, Kotlabova K, Dvorakova L, Krofta L, Sirc J. Postnatal Expression Profile of microRNAs Associated with Cardiovascular and Cerebrovascular Diseases in Children at the Age of 3 to 11 Years in Relation to Previous Occurrence of Pregnancy-Related Complications. Int J Mol Sci 2019; 20:ijms20030654. [PMID: 30717412 PMCID: PMC6387366 DOI: 10.3390/ijms20030654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 01/29/2019] [Accepted: 01/30/2019] [Indexed: 02/07/2023] Open
Abstract
Children descending from pregnancies complicated by gestational hypertension (GH), preeclampsia (PE) or fetal growth restriction (FGR) have a lifelong cardiovascular risk. The aim of the study was to verify if pregnancy complications induce postnatal alterations in gene expression of microRNAs associated with cardiovascular/cerebrovascular diseases. Twenty-nine microRNAs were assessed in peripheral blood, compared between groups, and analyzed in relation to both aspects, the current presence of cardiovascular risk factors and cardiovascular complications and the previous occurrence of pregnancy complications with regard to the clinical signs, dates of delivery, and Doppler ultrasound examination. The expression profile of miR-21-5p differed between controls and children with a history of uncomplicated pregnancies with abnormal clinical findings. Abnormal expression profile of multiple microRNAs was found in children affected with GH (miR-1-3p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-23a-3p, miR-26a-5p, miR-29a-3p, miR-103a-3p, miR-125b-5p, miR-126-3p, miR-133a-3p, miR-146a-5p, miR-181a-5p, miR-195-5p, and miR-342-3p), PE (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-103a-3p, miR-133a-3p, miR-342-3p), and FGR (miR-17-5p, miR-126-3p, miR-133a-3p). The index of pulsatility in the ductus venosus showed a strong positive correlation with miR-210-3p gene expression in children exposed to PE and/or FGR. Any of changes in epigenome (up-regulation of miR-1-3p and miR-133a-3p) that were induced by pregnancy complications are long-acting and may predispose children affected with GH, PE, or FGR to later development of cardiovascular/cerebrovascular diseases. Novel epigenetic changes (aberrant expression profile of microRNAs) appeared in a proportion of children that were exposed to GH, PE, or FGR. Screening of particular microRNAs may stratify a highly risky group of children that might benefit from implementation of early primary prevention strategies.
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Affiliation(s)
- Ilona Hromadnikova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Katerina Kotlabova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Lenka Dvorakova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 10000 Prague, Czech Republic.
| | - Ladislav Krofta
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
| | - Jan Sirc
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 14700 Prague, Czech Republic.
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van de Worp WRPH, Theys J, van Helvoort A, Langen RCJ. Regulation of muscle atrophy by microRNAs: 'AtromiRs' as potential target in cachexia. Curr Opin Clin Nutr Metab Care 2018; 21:423-429. [PMID: 30198917 DOI: 10.1097/mco.0000000000000503] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To provide an overview and describe the mode of action of miRNAs recently implicated in muscle atrophy, and discuss the challenges to explore their potential as putative therapeutic targets in cachexia. RECENT FINDINGS Recent work showed differentially expressed miRNAs in skeletal muscle of patients with cachexia-associated diseases. Studies using experimental models revealed miRNA regulation of the anabolic IGF-1 and catabolic TGF- β/myostatin pathways, and downstream protein synthesis and proteolysis signaling in control of muscle mass. SUMMARY Cachexia is a complex metabolic condition associated with progressive body weight loss, wasting of skeletal muscle mass and decrease in muscle strength. MiRNAs play a central role in post-transcriptional gene regulation by targeting mRNAs, thereby coordinating and fine-tuning many cellular processes. MiRNA expression profiling studies of muscle biopsies have revealed differentially expressed miRNAs in patients with low muscle mass or cachexia. Evaluation in experimental models has revealed muscle atrophy, inhibition of protein synthesis and activation of proteolysis in response to modulation of specific miRNAs, termed 'atromiRs' in this review. These exciting findings call for further studies aimed at exploring the conservation of differentially expressed miRNAs across diseases accompanied by cachexia, identification of miRNA clusters and targets involved in muscle atrophy, and probing whether these miRNAs might be potential therapeutic targets for cachexia.
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Affiliation(s)
| | - Jan Theys
- Department of Radiation Oncology, GROW, Maastricht University Medical Center+, Maastricht
| | - Ardy van Helvoort
- Department of Respiratory Medicine, NUTRIM
- Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, the Netherlands
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Chaillou T. Skeletal Muscle Fiber Type in Hypoxia: Adaptation to High-Altitude Exposure and Under Conditions of Pathological Hypoxia. Front Physiol 2018; 9:1450. [PMID: 30369887 PMCID: PMC6194176 DOI: 10.3389/fphys.2018.01450] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 09/24/2018] [Indexed: 01/16/2023] Open
Abstract
Skeletal muscle is able to modify its size, and its metabolic/contractile properties in response to a variety of stimuli, such as mechanical stress, neuronal activity, metabolic and hormonal influences, and environmental factors. A reduced oxygen availability, called hypoxia, has been proposed to induce metabolic adaptations and loss of mass in skeletal muscle. In addition, several evidences indicate that muscle fiber-type composition could be affected by hypoxia. The main purpose of this review is to explore the adaptation of skeletal muscle fiber-type composition to exposure to high altitude (ambient hypoxia) and under conditions of pathological hypoxia, including chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF) and obstructive sleep apnea syndrome (OSAS). The muscle fiber-type composition of both adult animals and humans is not markedly altered during chronic exposure to high altitude. However, the fast-to-slow fiber-type transition observed in hind limb muscles during post-natal development is impaired in growing rats exposed to severe altitude. A slow-to-fast transition in fiber type is commonly found in lower limb muscles from patients with COPD and CHF, whereas a transition toward a slower fiber-type profile is often found in the diaphragm muscle in these two pathologies. A slow-to-fast transformation in fiber type is generally observed in the upper airway muscles in rodent models of OSAS. The factors potentially responsible for the adaptation of fiber type under these hypoxic conditions are also discussed in this review. The impaired locomotor activity most likely explains the changes in fiber type composition in growing rats exposed to severe altitude. Furthermore, chronic inactivity and muscle deconditioning could result in the slow-to-fast fiber-type conversion in lower limb muscles during COPD and CHF, while the factors responsible for the adaptation of muscle fiber type during OSAS remain hypothetical. Finally, the role played by cellular hypoxia, hypoxia-inducible factor-1 alpha (HIF-1α), and other molecular regulators in the adaptation of muscle fiber-type composition is described in response to high altitude exposure and conditions of pathological hypoxia.
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Affiliation(s)
- Thomas Chaillou
- School of Health Sciences, Örebro University, Örebro, Sweden
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Martín AI, Gómez-SanMiguel AB, Priego T, López-Calderón A. Formoterol treatment prevents the effects of endotoxin on muscle TNF/NF-kB, Akt/mTOR, and proteolytic pathways in a rat model. Role of IGF-I and miRNA 29b. Am J Physiol Endocrinol Metab 2018; 315:E705-E714. [PMID: 29969314 DOI: 10.1152/ajpendo.00043.2018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Inflammatory diseases are associated with muscle wasting as a result of an increase in proteolysis. The purpose of this study was to elucidate whether administration of a β2 adrenergic agonist, formoterol, was able to prevent the acute effects of sepsis induced by liposaccharide (LPS) injection on rat gastrocnemius muscle and to evaluate the possible roles of corticosterone, IGF-I, miR-23a, and miR-29b. For this purpose, male Wistar rats were injected with LPS and/or formoterol. Formoterol treatment decreased LPS-induced increase in serum corticosterone, TNFα upregulation, and NF-κB(p65) and Forkhead box protein O1 activation in the gastrocnemius. Atrogin-1, muscle RING-finger protein-1, microtubule-associated protein-1 light chain 3b (LC3b), and the lipidation of LC3b-I to LC3b-II were increased by LPS, and formoterol blocked these effects. Serum IGF-I and its mRNA levels in the gastrocnemius were decreased, whereas mecano growth factor and IGF binding protein 3 mRNA levels were increased in the rats injected with LPS but not in the rats that received LPS and formoterol. Similarly, LPS decreased Akt and mammalian target of rapamycin phosphorylation, and formoterol blocked these decreases. Finally, miR-29b expression in the gastrocnemius was upregulated by endotoxin injection, whereas miR-23a was not significantly different. Formoterol treatment did not significantly modify LPS-induced increase in muscle miR-29b. Furthermore, in control rats formoterol increased the expression of this miRNA. We conclude that formoterol decreases endotoxin-induced inflammation and proteolysis in rat skeletal muscle. Those responses can be a direct effect of β2 adrenergic receptor stimulation or/and of blocking the effects of LPS on corticosterone and IGF-I. Muscle miR-23a and -29b do not seem to play an important role in those responses.
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Affiliation(s)
- Ana Isabel Martín
- Department of Physiology, Faculty of Medicine, Complutense University , Madrid , Spain
| | | | - Teresa Priego
- Department of Physiology, Faculty of Medicine, Complutense University , Madrid , Spain
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The circulating non-coding RNA landscape for biomarker research: lessons and prospects from cardiovascular diseases. Acta Pharmacol Sin 2018; 39:1085-1099. [PMID: 29877319 DOI: 10.1038/aps.2018.35] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 01/20/2018] [Indexed: 12/21/2022]
Abstract
Pervasive transcription of the human genome is responsible for the production of a myriad of non-coding RNA molecules (ncRNAs) some of them with regulatory functions. The pivotal role of ncRNAs in cardiovascular biology has been unveiled in the last decade, starting from the characterization of the involvement of micro-RNAs in cardiovascular development and function, and followed by the use of circulating ncRNAs as biomarkers of cardiovascular diseases. The human non-coding secretome is composed by several RNA species that circulate in body fluids and could be used as biomarkers for diagnosis and outcome prediction. In cardiovascular diseases, secreted ncRNAs have been described as biomarkers of several conditions including myocardial infarction, cardiac failure, and atrial fibrillation. Among circulating ncRNAs, micro-RNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been proposed as biomarkers in different cardiovascular diseases. In comparison with standard biomarkers, the biochemical nature of ncRNAs offers better stability and flexible storage conditions of the samples, and increased sensitivity and specificity. In this review we describe the current trends and future prospects of the use of the ncRNA secretome components as biomarkers of cardiovascular diseases, including the opening questions related with their secretion mechanisms and regulatory actions.
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Hu B, Cai H, Zheng R, Yang S, Zhou Z, Tu J. Long non-coding RNA 657 suppresses hepatocellular carcinoma cell growth by acting as a molecular sponge of miR-106a-5p to regulate PTEN expression. Int J Biochem Cell Biol 2017; 92:34-42. [DOI: 10.1016/j.biocel.2017.09.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/11/2017] [Accepted: 09/13/2017] [Indexed: 02/07/2023]
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