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Reduction of Cardiac TGFß-mediated Profibrotic Events by Inhibition of Hsp90 With Engineered Protein

Abstract: Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGF?-Smad2/3 signaling. Targeting the ubiquitous TGF? 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 TGF? 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 TGF?RI-Hsp90 complex, resulting in a decrease in TGF? 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 TGF?-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: J Mol Cell Cardiol , 123, 75-87 Oct 2018

Editorial: Elsevier

 Año de publicación: 2018

Nº de páginas: 13

Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.yjmcc.2018.08.016

ISSN: 0022-2828,1095-8584

Proyecto español: BIO2015-72124-EXP ; BIO2016-77367-R

Url de la publicación: https://www.doi.org/10.1016/j.yjmcc.2018.08.016

Autores/as

CÁCERES, R A

CHAVEZ, T

DAVID MAESTRO LAVIN

BOLADO, P

MADRAZO, F.

AIRES, A.

CORTAJARENA, A.L.