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Extracellular heat shock protein 90 binding to TGFbeta receptor I participates in TGFbeta-mediated collagen production in myocardial fibroblasts

Abstract: The pathological remodeling heart shows an increase in left ventricular mass and an excess of extracellular matrix deposition that can over time cause heart failure. Transforming growth factor ? (TGF?) is the main cytokine controlling this process. The molecular chaperone heat shock protein 90 (Hsp90) has been shown to play a critical role in TGF? signaling by stabilizing the TGF? signaling cascade. We detected extracellular Hsp90 in complex with TGF? receptor I (TGF?RI) in fibroblasts and determined a close proximity between both proteins suggesting a potential physical interaction between the two at the plasma membrane. This was supported by in silico studies predicting Hsp90 dimers and TGF?RI extracellular domain interaction. Both, Hsp90aa1 and Hsp90ab1 isoforms participate in TGF?RI complex. Extracellular Hsp90 inhibition lessened the yield of collagen production as well as the canonical TGF? signaling cascade, and collagen protein synthesis was drastically reduced in Hsp90aa1 KO mice. These observations together with the significant increase in activity of Hsp90 at the plasma membrane pointed to a functional cooperative partnership between Hsp90 and TGF?RI in the fibrotic process. We propose that a surface population of Hsp90 extracellularly binds TGF?RI and this complex behaves as an active participant in collagen production in TGF?-activated fibroblasts. We also offer an in vivo insight into the role of Hsp90 and its isoforms during cardiac remodeling in murine aortic banding model suffering from pathological cardiac remodeling and detect circulating Hsp90 overexpressed in remodeling mice.

 Autoría: García R., Merino D., Gómez J., Nistal J., Hurlé M., Cortajarena A., Villar A.,

 Fuente: Cellular Signalling, 2016, 28(10), 1563-1579

 Editorial: Elsevier Science Ltd

 Año de publicación: 2016

 Nº de páginas: 17

 Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.cellsig.2016.07.003

 ISSN: 0898-6568,1873-3913

 Proyecto español: SAF2013-47434-Retos