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 β (TGFβ) is the main cytokine controlling this process. The molecular chaperone heat shock protein 90 (Hsp90) has been shown to play a critical role in TGFβ signaling by stabilizing the TGFβ signalingcascade.Wedetected extracellular Hsp90 incomplex withTGFβreceptorI(TGFβRI)infibroblastsanddeterminedacloseproximitybetweenbothproteinssuggesting apotentialphysicalinteractionbetweenthetwoattheplasmamembrane.Thiswassupportedbyinsilicostudies predicting Hsp90 dimers and TGFβRI extracellular domain interaction. Both, Hsp90aa1 and Hsp90ab1 isoforms participate in TGFβRI complex. Extracellular Hsp90 inhibition lessened the yield of collagen production as well as the canonical TGFβ signaling cascade, and collagen protein synthesis was drastically reduced in Hsp90aa1 KOmice.These observations together with the significant increase in activity of Hsp90 at the plasma membrane pointed to a functional cooperative partnership between Hsp90 and TGFβRI in the fibrotic process. We propose thatasurfacepopulationofHsp90extracellularlybindsTGFβRIandthiscomplexbehavesasanactiveparticipant in collagen productioninTGFβ-activatedfibroblasts.WealsoofferaninvivoinsightintotheroleofHsp90andits isoforms during cardiac remodeling in murine aortic banding model suffering from pathological cardiac remodeling and detect circulating Hsp90 overexpressed in remodeling mice.