title: NFATc4 and myocardin synergistically up-regulate the expression of LTCC α1C in ET-1-induced cardiomyocyte hypertrophy.
abstract: OBJECTIVE
  Dysregulation of Ca(2+) is a central cause of cardiac hypertrophy. The α1C subunit of L-type Ca(2+) channel (LTCC) is a pore-forming protein which is responsible for the voltage-dependent channel gating and channel selectivity for Ca(2+). Myocardin and nuclear factor of activated T-cells c4 (NFATc4) are two key transcription factors in cardiac hypertrophy. We aimed to investigate the underlying mechanism of the transcriptional regulation of LTCC α1C by myocardin and NFATc4 in hypertrophic cardiomyocytes.
  
  
  METHODS
  Endothelin-1 (ET-1) was used to induce cardiomyocyte hypertrophy. Cyclosporin A (CSA) was used to block the activation of calcineurin/NFATc4 pathway in ET-1-treated cardiomyocytes and the expression of LTCC α1C were examined. Overexpression or RNAi interfering experiments were performed to investigate the effects of NFATc4 or myocardin on the transcriptional regulation of LTCC α1C. Interactions between NFATc4 and myocardin or the association of NFATc4 with myocardin promoter were assessed via Co-IP or ChIP assays respectively.
  
  
  RESULTS
  In the present study, we found that ET-1 stimulated LTCC α1C transcription in neonatal rat cardiomyocytes partially via the activation of calcineurin/NFATc4 pathway. Overexpression of NFATc4 or myocardin promoted LTCC α1C expression in cardiomyocytes. Ca(2+) channel blocker verapamil or knockdown of α1C inhibited myocardin-induced cardiomyocyte hypertrophy. Further studies showed that NFATc4 interacted with myocardin to synergistically activate the expression of LTCC α1C, moreover, NFATc4 activated myocardin expression by binding to its promoter.
  
  
  CONCLUSIONS
  Our results suggest a novel mechanism of the transcriptional regulation of LTCC α1C by synergistic activities of NFATc4 and myocardin in ET-1-induced cardiomyocyte hypertrophy.
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Hong-Peng
authors.initials: HP
authors.lastname: He
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Hui-Qin
authors.initials: HQ
authors.lastname: Gong
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Ma
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institute of Biology and Medicine, Wuhan University of Science and Technology, PR China, 430000.
authors.forename: Dong-Sun
authors.initials: DS
authors.lastname: Cao
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457. Electronic address: wn929@tust.edu.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, PR China, 300457; Institute of Biology and Medicine, Wuhan University of Science and Technology, PR China, 430000. Electronic address: tony@tust.edu.cn.
authors.forename: Tong-Cun
authors.initials: TC
authors.lastname: Zhang
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D000099251:Myocardin
chemical_list: D020746:Calcium Channels, L-Type; D019332:Endothelin-1; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin; C477593:Nfatc4 protein, rat
keywords: Cardiomyocyte hypertrophy; Endothelin-1; L-type Ca(2+) channel; Myocardin; Nuclear factor of activated T-cells c4