title: Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy.
abstract: Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference betweenin vivoandin vitroresults, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
authors.forename: Ritwik
authors.initials: R
authors.lastname: Datta
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
authors.forename: Trisha
authors.initials: T
authors.lastname: Bansal
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
authors.forename: Santanu
authors.initials: S
authors.lastname: Rana
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
authors.forename: Kaberi
authors.initials: K
authors.lastname: Datta
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
authors.forename: Ratul
authors.initials: R
authors.lastname: Datta Chaudhuri
authors.affiliation: Division of Virology, National Institute of Cholera and Enteric Diseases, Kolkata, India.
authors.forename: Mamta
authors.initials: M
authors.lastname: Chawla-Sarkar
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, Kolkata, India sagartirtha.sarkar@gmail.com.
authors.forename: Sagartirtha
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D061988:Proteasome Inhibitors; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D025801:Ubiquitin; C112765:tanespimycin; D003094:Collagen; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex
keywords: Hsp90; STAT-3; cardiac hypertrophy; collagen; myocyte-fibroblast cross talk