title: Electrical field stimulation induces cardiac fibroblast proliferation through the calcineurin-NFAT pathway.
abstract: Most cardiac diseases are associated with fibrosis. Calcineurin (CaN) is regulated by Ca(2+)/calmodulin (CaM). The CaN-NFAT (nuclear factor of activated T cell) pathway is involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effect on myocardial fibrosis remains unclear. The present study investigates whether the CaN-NFAT pathway is involved in cardiac fibroblast (CF) proliferation induced by electrical field stimulation (EFS), which recently became a popular treatment for heart failure and cardiac tissue engineering. CF proliferation was evaluated by a cell survival assay (MTT) and cell counts. Myocardial fibrosis was assessed by collagen I and collagen III protein expression. Green fluorescent protein (GFP)-tagged NFAT was used to detect NFAT nuclear translocation. CF proliferation, myocardial fibrosis, CaN activity, and NFAT nuclear translocation were enhanced by EFS. More importantly, these effects were abolished by CaN inhibitors, dominant negative CaN (DN-CaN), and CaN gene silenced with siRNA. Furthermore, buffering intracellular Ca(2+) with BAPTA-AM and blocking Ca(2+) influx with nifedipine suppressed EFS-induced increase in intracellular Ca(2+) and CF proliferation. These results suggested that the CaN-NFAT pathway mediates CF proliferation, and that the CaN-NFAT pathway might be a possible therapeutic target for EFS-induced myocardial fibrosis and cardiac tissue engineering.
authors.affiliation: Department of Pharmacology, Nantong University Medical College, Nantong, P.R. China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiang-Fan
authors.initials: XF
authors.lastname: Chen
authors.forename: Yun-Jian
authors.initials: YJ
authors.lastname: Bao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D050778:NFATC Transcription Factors; D019703:Calcineurin; D002118:Calcium