title: Exploring Regulatory Mechanisms of Atrial Myocyte Hypertrophy of Mitral Regurgitation through Gene Expression Profiling Analysis: Role of NFAT in Cardiac Hypertrophy.
abstract: BACKGROUND
  Left atrial enlargement in mitral regurgitation (MR) predicts a poor prognosis. The regulatory mechanisms of atrial myocyte hypertrophy of MR patients remain unknown.
  
  
  RESULTS
  This study comprised 14 patients with MR, 7 patients with aortic valve disease (AVD), and 6 purchased samples from normal subjects (NC). We used microarrays, enrichment analysis and quantitative RT-PCR to study the gene expression profiles in the left atria. Microarray results showed that 112 genes were differentially up-regulated and 132 genes were differentially down-regulated in the left atria between MR patients and NC. Enrichment analysis of differentially expressed genes demonstrated that "NFAT in cardiac hypertrophy" pathway was not only one of the significant associated canonical pathways, but also the only one predicted with a non-zero score of 1.34 (i.e. activated) through Ingenuity Pathway Analysis molecule activity predictor. Ingenuity Pathway Analysis Global Molecular Network analysis exhibited that the highest score network also showed high association with cardiac related pathways and functions. Therefore, 5 NFAT associated genes (PPP3R1, PPP3CB, CAMK1, MEF2C, PLCE1) were studies for validation. The mRNA expressions of PPP3CB and MEF2C were significantly up-regulated, and CAMK1 and PPP3R1 were significantly down-regulated in MR patients compared to NC. Moreover, MR patients had significantly increased mRNA levels of PPP3CB, MEF2C and PLCE1 compared to AVD patients. The atrial myocyte size of MR patients significantly exceeded that of the AVD patients and NC.
  
  
  CONCLUSIONS
  Differentially expressed genes in the "NFAT in cardiac hypertrophy" pathway may play a critical role in the atrial myocyte hypertrophy of MR patients.
authors.affiliation: Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Chang
authors.affiliation: Division of Cardiology and Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Mien-Cheng
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Jen-Ping
authors.initials: JP
authors.lastname: Chang
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Hsien-Da
authors.initials: HD
authors.lastname: Huang
authors.affiliation: Division of Cardiology and Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Ho
authors.affiliation: Division of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kuo-Li
authors.initials: KL
authors.lastname: Pan
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yao-Kuang
authors.initials: YK
authors.lastname: Huang
authors.affiliation: Division of Cardiology and Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Wu
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000503:physiopathology; D000082882:Bicuspid Aortic Valve Disease; D019703:Calcineurin / Q000096:biosynthesis* / Q000235:genetics; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000096:biosynthesis* / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006349:Heart Valve Diseases / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D064326:MEF2 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D008944:Mitral Valve Insufficiency / Q000235:genetics / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology; D054801:Phosphoinositide Phospholipase C / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D012333:RNA, Messenger; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D019703:Calcineurin; C525674:PPP3CB protein, human; C525676:PPP3R1 protein, human; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon