Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Mol Cell Biol. 2017 Mar 1;37(6):e00611-16. doi: 10.1128/MCB.00611-16. Print 2017 Mar 15.


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 between in vivo and in vitro results, 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.

Keywords: Hsp90; STAT-3; cardiac hypertrophy; collagen; myocyte-fibroblast cross talk.

MeSH terms

  • Animals
  • Benzoquinones / pharmacology
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cell Movement / drug effects
  • Collagen / metabolism*
  • Down-Regulation / drug effects
  • Exosomes / drug effects
  • Exosomes / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism*
  • I-kappa B Kinase / metabolism
  • Interleukin-6 / metabolism
  • Lactams, Macrocyclic / pharmacology
  • Male
  • Models, Biological
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Stability / drug effects
  • Rats, Wistar
  • STAT3 Transcription Factor / metabolism*
  • Transcription Factor RelA / metabolism
  • Ubiquitin / metabolism
  • Up-Regulation* / drug effects


  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Interleukin-6
  • Lactams, Macrocyclic
  • Proteasome Inhibitors
  • STAT3 Transcription Factor
  • Transcription Factor RelA
  • Ubiquitin
  • tanespimycin
  • Collagen
  • I-kappa B Kinase
  • Proteasome Endopeptidase Complex