David Y Chiang1, Min Zhang2, Niels Voigt3, Katherina M Alsina4, Heinz Jakob5, James F Martin6, Dobromir Dobrev3, Xander H T Wehrens7, Na Li8. 1. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA. 2. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA. 3. Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany. 4. Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX, USA. 5. Department of Thoracic and Cardiovascular Surgery, University Hospital, Essen, Germany. 6. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA; Texas Heart Institute Houston, TX, USA. 7. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA. 8. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA. Electronic address: nal@bcm.edu.
Abstract
BACKGROUND: The molecular mechanisms underlying the early development of atrial fibrillation (AF) remain poorly understood. Emerging evidence suggests that abnormal epigenetic modulation via microRNAs (miRNAs) might be involved in the pathogenesis of paroxysmal AF (pAF). OBJECTIVE: To identify key molecular changes associated with pAF, we conducted state-of-the-art transcriptomic studies to identify the abnormal miRNA-mRNA interactions potentially driving AF development. METHODS: High-quality total RNA including miRNA was isolated from atrial biopsies of age-matched and sex-matched pAF patients and control patients in sinus rhythm (SR; n=4 per group) and used for RNA-sequencing and miRNA microarray. Results were analyzed bioinformatically and validated using quantitative real-time (qRT)-PCR and 3'UTR luciferase reporter assays. RESULTS: 113 genes and 49 miRNAs were differentially expressed (DE) in pAF versus SR patients. Gene ontology analysis revealed that most of the DE genes were involved in the "gonadotropin releasing hormone receptor pathway" and "p53 pathway". Of these DE genes, bioinformatic analyses identified 23 pairs of putative miRNA-mRNA interactions that were altered in pAF (involving 15 miRNAs and 17 mRNAs). Using qRT-PCR and 3'UTR luciferase reporter assays, the interaction between upregulation of miR-199a-5p and downregulation of FKBP5 was confirmed in samples from pAF patients. CONCLUSION: Our combined transcriptomic analysis and miRNA microarray study of atrial samples from pAF patients revealed novel pathways and miRNA-mRNA regulations that may be relevant in the development of pAF. Future studies are required to investigate the potential involvement of the gonadotropin releasing hormone receptor and p53 pathways in AF pathogenesis.
BACKGROUND: The molecular mechanisms underlying the early development of atrial fibrillation (AF) remain poorly understood. Emerging evidence suggests that abnormal epigenetic modulation via microRNAs (miRNAs) might be involved in the pathogenesis of paroxysmal AF (pAF). OBJECTIVE: To identify key molecular changes associated with pAF, we conducted state-of-the-art transcriptomic studies to identify the abnormal miRNA-mRNA interactions potentially driving AF development. METHODS: High-quality total RNA including miRNA was isolated from atrial biopsies of age-matched and sex-matched pAF patients and control patients in sinus rhythm (SR; n=4 per group) and used for RNA-sequencing and miRNA microarray. Results were analyzed bioinformatically and validated using quantitative real-time (qRT)-PCR and 3'UTR luciferase reporter assays. RESULTS: 113 genes and 49 miRNAs were differentially expressed (DE) in pAF versus SRpatients. Gene ontology analysis revealed that most of the DE genes were involved in the "gonadotropin releasing hormone receptor pathway" and "p53 pathway". Of these DE genes, bioinformatic analyses identified 23 pairs of putative miRNA-mRNA interactions that were altered in pAF (involving 15 miRNAs and 17 mRNAs). Using qRT-PCR and 3'UTR luciferase reporter assays, the interaction between upregulation of miR-199a-5p and downregulation of FKBP5 was confirmed in samples from pAF patients. CONCLUSION: Our combined transcriptomic analysis and miRNA microarray study of atrial samples from pAF patients revealed novel pathways and miRNA-mRNA regulations that may be relevant in the development of pAF. Future studies are required to investigate the potential involvement of the gonadotropin releasing hormone receptor and p53 pathways in AF pathogenesis.
Authors: Alison M Thomas; Claudia P Cabrera; Malcolm Finlay; Kulvinder Lall; Muriel Nobles; Richard J Schilling; Kristie Wood; Charles A Mein; Michael R Barnes; Patricia B Munroe; Andrew Tinker Journal: Physiol Genomics Date: 2019-06-07 Impact factor: 3.107
Authors: Ann P Quick; Qiongling Wang; Leonne E Philippen; Giselle Barreto-Torres; David Y Chiang; David Beavers; Guoliang Wang; Maha Khalid; Julia O Reynolds; Hannah M Campbell; Jordan Showell; Mark D McCauley; Arjen Scholten; Xander H T Wehrens Journal: Circ Res Date: 2016-10-11 Impact factor: 17.367
Authors: Hannah Campbell; Yuriana Aguilar-Sanchez; Ann P Quick; Dobromir Dobrev; Xander H T Wehrens Journal: Cardiovasc Res Date: 2021-08-29 Impact factor: 10.787
Authors: Mary E Haywood; Andrea Cocciolo; Kadijah F Porter; Evgenia Dobrinskikh; Dobromir Slavov; Sharon L Graw; T Brett Reece; Amrut V Ambardekar; Michael R Bristow; Luisa Mestroni; Matthew R G Taylor Journal: J Mol Cell Cardiol Date: 2020-01-18 Impact factor: 5.000