Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered proteinReduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered proteinCáceres RA, Chavez T, Maestro D, Palanca AR, Bolado P, Madrazo F, Aires A, Cortajarena AL, Villar AV2018-09-30T22:00:00Z<h3>​Abstract </h3><p><br></p><p>Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFβ-Smad2/3 signaling. Targeting the ubiquitous TGFβ leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFβ signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFβRI-Hsp90 complex, resulting in a decrease in TGFβ signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFβ-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.<br></p><p>​J Mol Cell Cardiol. 2018 Oct;123:75-87. doi: 10.1016/j.yjmcc.2018.08.016.<br></p>237