title: PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling.
abstract: PICOT (protein kinase C-interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. The combined analyses of glutathione S-transferase pull-down experiments and mass spectrometry enabled us to determine that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half (PICOT-C). It was also shown that PICOT colocalizes with MLP in the Z-disc. MLP is known to play a role in anchoring calcineurin to the Z-disc in the sarcomere, which is critical for calcineurin-NFAT (nuclear factor of activated T cells) signaling. We, therefore, suggested that PICOT may affect calcineurin-NFAT signaling through its interaction with MLP. Consistent with this hypothesis, PICOT, or more specifically PICOT-C, abrogated phenylephrine-induced increases in calcineurin phosphatase activity, NFAT dephosphorylation/nuclear translocation, and NFAT-dependent transcriptional activation in neonatal cardiomyocytes. In addition, pressure overload-induced upregulation of NFAT target genes was significantly diminished in the hearts of PICOT-overexpressing transgenic mice. PICOT interfered with MLP-calcineurin interactions in a dose-dependent manner. Moreover, calcineurin was displaced from the Z-disc, concomitant with an abrogated interaction between calcineurin and MLP, in the hearts of PICOT transgenic mice. Replenishment of MLP restored the hypertrophic responses and the increase in calcineurin phosphatase activity that was inhibited by PICOT in phenylephrine-treated cardiomyocytes. Finally, PICOT-C inhibited cardiac hypertrophy to an extent that was comparable to that of full-length PICOT. Taken together, these data suggest that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin-NFAT signaling via disruption of the MLP-calcineurin interaction.
authors.affiliation: Global Research Laboratory and Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Ji Myoung
authors.initials: JM
authors.lastname: Kim
authors.forename: Hyeseon
authors.initials: H
authors.lastname: Cha
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.forename: Jaeho
authors.initials: J
authors.lastname: Park
authors.forename: Soo-Hyeon
authors.initials: SH
authors.lastname: Yun
authors.forename: Eun-Seon
authors.initials: ES
authors.lastname: Ju
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Jeon
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology; D048429:Cell Size; D002478:Cells, Cultured; D060588:LIM Domain Proteins; D040542:Mechanotransduction, Cellular; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013879:Thioredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D002316:Cardiotonic Agents; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D011993:Recombinant Fusion Proteins; C090114:cysteine and glycine-rich protein 3; D010656:Phenylephrine; D013879:Thioredoxins; C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases