title: Phenylephrine promotes cardiac fibroblast proliferation through calcineurin-NFAT pathway.
abstract: Ca(2+)/calmodulin-dependent calcineurin (CaN) plays an important role in various Ca(+2) signaling pathways, among which are those involved in cardiac diseases. It has also been shown that a heightened sympathetic tone accelerates the development of heart failure. The present study investigates whether the CaN-mediated nuclear factor of activated T-cells (NFAT) pathway is involved in cultured neonatal rat cardiac fibroblast proliferation induced by phenylephrine. CF proliferation was assessed by a cell survival assay and cell counts. Green fluorescent protein-tagged NFAT3 was used to determine the cellular location of NFAT3. CaN activity and protein levels were also determined by an activity assay kit and Western blotting, respectively. Results showed that phenylephrine promoted CF proliferation, which was abolished by α1-adrenergic receptor antagonist (prazosin), a blocker of Ca(+2) influx (nifedipine), an intracellular Ca(2+) buffer (BAPTA-AM), CaN inhibitors (cyclosporin A and FK506), and over-expression of dominant negative CaN. Phenylephrine activated CaN and evoked NFAT3 nuclear translocation, both of which were blocked by cyclosporine A (CsA) or over-expression of dominant negative CaN. These results suggest that the Ca(2+)/CaN/NFAT pathway mediates PE-induced CF proliferation, and this pathway might be a possible therapeutic target in cardiac fibrosis.
authors.affiliation: Department of Pharmacy, Nantong University Affiliated Hospital, Nantong, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Yan Cheng Institute of Health Science.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, Nantong, P. R. China.
authors.forename: Yunxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Nantong University School of Pharmacy, 19 Qi Xiu Road, Nantong, 226001, People's Republic of China, zhuwz@ntu.edu.cn.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D017136:Ion Transport; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D016572:Cyclosporine; D019703:Calcineurin; D002118:Calcium