| First Author | Cáceres RA | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 123 |
| Pages | 75-87 | PubMed ID | 30193958 |
| Mgi Jnum | J:266914 | Mgi Id | MGI:6200476 |
| Doi | 10.1016/j.yjmcc.2018.08.016 | Citation | Caceres RA, et al. (2018) Reduction of cardiac TGFbeta-mediated profibrotic events by inhibition of Hsp90 with engineered protein. J Mol Cell Cardiol 123:75-87 |
| abstractText | Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFbeta-Smad2/3 signaling. Targeting the ubiquitous TGFbeta 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 TGFbeta 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 TGFbetaRI-Hsp90 complex, resulting in a decrease in TGFbeta 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 TGFbeta-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo. |
