Differentially expressed miRNAs in circulating exosomes between atrial fibrillation and sinus rhythm.

Background Exosomes are small (30-150 nm) membrane vesicles released by cells that transmit intercellular information. As one of the contents of exosomes, microRNAs (miRNAs) may play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs potentially function as biomarkers in AF, as shown in many other diseases. Methods To identify the different expression level of plasma exosomal miRNAs between persistent AF and sinus rhythm (SR) patients, we performed high-throughput sequencing of small RNAs in the exosomes of AF (n=4) and SR (n=4) patients. Target genes of the DE miRNAs were predicted and put into gene ontology analysis and pathway analysis. In the validation phase, we performed quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) of 6 of the DE miRNAs in AF (n=40) and SR (n=20) patients. Univariate and multivariate logistic analysis were used to analyze risk factors of AF. Results With high-throughput sequencing, we revealed 39 differentially expressed (DE) miRNAs in circulating exosomes. We validated 4 of the DE plasma exosomal miRNAs (miR-483-5p, miR-142-5p, miR-223-3p, miR-223-5p) using qRT-PCR. Univariate logistic analysis shows miR-483-5p, miR-142-5p, miR-223-3p are related with AF, while multivariate logistic analysis suggests miR-483-5p is independently in correlation with AF. Conclusions This discovery opens up a new perspective in the complicated mechanism underlying AF and the DE plasma exosomal miRNAs exert enormous potential of acting as biomarkers in assessing severity or prognostic of AF and help selecting therapeutic strategy.

[1]  Dan Hu,et al.  Early diagnostic value of circulating microRNAs in patients with suspected acute myocardial infarction , 2019, Journal of cellular physiology.

[2]  B. Joung,et al.  Expression of miRNAs in circulating exosomes derived from patients with persistent atrial fibrillation , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  L. Eliasson,et al.  miR-483-5p associates with obesity and insulin resistance and independently associates with new onset diabetes mellitus and cardiovascular disease , 2018, PloS one.

[4]  Jiao Liu,et al.  Reduced exosome miR‐425 and miR‐744 in the plasma represents the progression of fibrosis and heart failure , 2018, The Kaohsiung journal of medical sciences.

[5]  Jimin Cao,et al.  Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation , 2018, Medical science monitor : international medical journal of experimental and clinical research.

[6]  Zhi-hong Zhao,et al.  SOX2-mediated inhibition of miR-223 contributes to STIM1 activation in phenylephrine-induced hypertrophic cardiomyocytes , 2017, Molecular and Cellular Biochemistry.

[7]  Y. Zhang,et al.  Suppression of microRNA-142-5p attenuates hypoxia-induced apoptosis through targeting SIRT7. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[8]  C. Drummond,et al.  MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes. , 2017, Gene.

[9]  Nami Kim,et al.  Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes , 2017, Scientific Reports.

[10]  B. Joung,et al.  P1562Exosome derived from atrial fibrillation patients prevents proarrhythmic remodeling by suppressing autophagy in pacing induced tachycardia model , 2017 .

[11]  Klaus Pantel,et al.  Liquid Biopsy: Current Status and Future Perspectives , 2017, Oncology Research and Treatment.

[12]  A. Lam,et al.  The search for atrial fibrillation and its impact on public health. , 2017, Swiss medical weekly.

[13]  P. Armstrong,et al.  Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome. , 2017, Atherosclerosis.

[14]  Qinyu Ge,et al.  No Significant Difference between Plasma miRNAs and Plasma-Derived Exosomal miRNAs from Healthy People , 2017, BioMed research international.

[15]  P. Kirchhof,et al.  Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration , 2017, Circulation.

[16]  Zhiqiang Gao,et al.  Progress in Exosome Isolation Techniques , 2017, Theranostics.

[17]  S. Mousavi,et al.  Glioblastoma: exosome and microRNA as novel diagnosis biomarkers , 2016, Cancer Gene Therapy.

[18]  H. Matsubara,et al.  Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma , 2016, Oncology reports.

[19]  B. Zhao,et al.  A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. , 2016, European heart journal.

[20]  Xiaohong Wang,et al.  MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts* , 2016, The Journal of Biological Chemistry.

[21]  A. Darzi,et al.  Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation , 2016, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[22]  G. Angelini,et al.  Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery , 2016, PloS one.

[23]  E. Marbán,et al.  Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology. , 2016, Annual review of physiology.

[24]  B. C. Bernardo,et al.  miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart. , 2015, Future medicinal chemistry.

[25]  S. Kääb,et al.  The Role of MicroRNAs in Antiarrhythmic Therapy for Atrial Fibrillation. , 2015, Arrhythmia & electrophysiology review.

[26]  Zhiqiang Ma,et al.  PD-1/PD-L1 expression on CD4+ T cells and myeloid DCs correlates with the immune pathogenesis of atrial fibrillation , 2015, Journal of cellular and molecular medicine.

[27]  M. Mayr,et al.  Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. , 2014, The Journal of clinical investigation.

[28]  Q. Sun,et al.  Expression of ALDH1 in breast invasive ductal carcinoma: an independent predictor of early tumor relapse , 2013, Cancer Cell International.

[29]  P. Doevendans,et al.  Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. , 2013, Stem cell research.

[30]  I. Sargent,et al.  Exosome-mediated delivery of siRNA in vitro and in vivo , 2012, Nature Protocols.

[31]  M. Cowley,et al.  Influence of atrial fibrillation on microRNA expression profiles in left and right atria from patients with valvular heart disease. , 2012, Physiological genomics.

[32]  N. Jablonski,et al.  Circulating microRNAs involved in multiple sclerosis , 2012, Molecular Biology Reports.

[33]  Xu Gao,et al.  MiR‐483‐5p controls angiogenesis in vitro and targets serum response factor , 2011, FEBS letters.

[34]  Hamid Cheshmi.  Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[35]  M. Wood,et al.  Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes , 2011, Nature Biotechnology.

[36]  Gerard Pasterkamp,et al.  Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. , 2010, Stem cell research.

[37]  C. Croce,et al.  MicroRNA-133 controls cardiac hypertrophy , 2007, Nature Medicine.

[38]  Junjie Xiao,et al.  Circulating Exosomes in Cardiovascular Diseases. , 2017, Advances in experimental medicine and biology.

[39]  F. Court,et al.  Exosomes: mediators of communication in eukaryotes. , 2013, Biological research.