title: Hyperphosphate-Induced Myocardial Hypertrophy through the GATA-4/NFAT-3 Signaling Pathway Is Attenuated by ERK Inhibitor Treatment.
abstract: OBJECTIVE
  Numerous epidemiological studies have associated elevated serum phosphorus levels with cardiovascular disease and the risk of death in the general population as well as in chronic kidney disease (CKD) and dialysis patients. In this study, we explored whether elevated phosphate conditions induce cardiac hypertrophy and attempted to identify the molecular and cellular mechanisms in the hypertrophic response.
  
  
  METHODS
  H9c2 myocardial cells were incubated in high-phosphate conditions to induce hypertrophy. Pathological hypertrophic responses were measured in terms of cell size, arrangement of actin filaments, and hypertrophy markers such as atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in myocardial cells. Several transcriptional factors involved in cardiac hypertrophy development were measured to investigate the molecular pathways involved in elevated phosphate-induced cardiac hypertrophy.
  
  
  RESULTS
  High-phosphate conditions induced cellular hypertrophy, marked by increased cell size, reorganization of actin filaments, and upregulation of both ANP and BNP in H9c2 cells. Both upstream calcineurin and downstream transcription factors, including GATA-4 and NFAT-3, were significantly increased under hyperphosphate conditions. Moreover, both MEK1/2 and ERK1/2 expression increased significantly, and cellular hypertrophy was markedly attenuated by U0126, an ERK1/2 inhibitor.
  
  
  CONCLUSIONS
  These results suggest that hyperphosphate conditions induce myocardial hypertrophy through the ERK signaling pathway in H9c2 cells. Our findings provide a link between the hyperphosphate-induced response and the ERK/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy. In view of the potent and selective activity of the ERK inhibitor U0126, this agent warrants further investigation as a candidate for preventing hyperphosphate-induced cardiac hypertrophy in CKD and dialysis patients.
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
authors.forename: Yao-Lung
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
authors.forename: Chiu-Ching
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
authors.forename: Chiz-Chung
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
authors.forename: Che-Yi
authors.initials: CY
authors.lastname: Chou
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Division of Nephrology and Kidney Institute, China Medical University Hospital, Taiwan, ROC ; School of Medicine, China Medical University, Taiwan, ROC.
authors.forename: I-Kuan
authors.initials: IK
authors.lastname: Wang
authors.affiliation: School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taiwan, ROC ; Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taiwan, ROC.
authors.forename: Dennis Jine-Yuan
authors.initials: DJ
authors.lastname: Hsieh
authors.affiliation: Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taiwan, ROC.
authors.forename: Gwo-Ping
authors.initials: GP
authors.lastname: Jong
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taiwan, ROC ; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Research Center for Biodiversity, China Medical University, Taiwan, ROC.
authors.forename: Chao-Min
authors.initials: CM
authors.lastname: Wang
keywords: Calcineurin; Cardiomyocyte hypertrophy; ERK inhibitor; Hyperphosphate