title: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha protects cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 signaling pathway.
abstract: Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is a crucial coregulator interacting with multiple transcriptional factors in the regulation of cardiac hypertrophy. The present study revealed that PGC-1α protected cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 (NFATc4) signaling pathway. Overexpression of PGC-1α by adenovirus infection prevented the increased protein and messenger RNA expression of NFATc4 in phenylephrine (PE)-treated hypertrophic cardiomyocytes, whereas knockdown of PGC-1α by RNA silencing augmented the expression of NFATc4. An interaction between PGC-1α and NFATc4 was observed in both the cytoplasm and nucleus of neonatal rat cardiomyocytes. Adenovirus PGC-1α prevented the nuclear import of NFATc4 and increased its phosphorylation level of NFATc4, probably through repressing the expression and activity of calcineurin and interfering with the interaction between calcineurin and NFATc4. On the contrary, PGC-1α silencing aggravated PE-induced calcineurin activation, NFATc4 dephosphorylation, and nuclear translocation. Moreover, the binding activity and transcription activity of NFATc4 to DNA promoter of brain natriuretic peptide were abrogated by PGC-1α overexpression but were enhanced by PGC-1α knockdown. The effect of PGC-1α on suppressing the calcinuerin-NFATc4 signaling pathway might at least partially contribute to the protective effect of PGC-1α on cardiomyocyte hypertrophy. These findings provide novel insights into the role of PGC-1α in regulation of cardiac hypertrophy.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Xue-Ping
authors.initials: XP
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China; Department of Pharmacology, School of Medicine, Jishou University, Jishou, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China. Electronic address: lizhm5@mail.sysu.edu.cn.
authors.forename: Zhuo-Ming
authors.initials: ZM
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, PR China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Pei-Qing
authors.initials: PQ
authors.lastname: Liu
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors