Actividad Investigadora
Reduction of cardiac TGF beta-mediated profibrotic events by inhibition of Hsp90 with engineered protein
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Autores de IDIVAL
Autores ajenos al IDIVAL
- Caceres, RA
- Chavez, T
- Aires, A
- Cortajarena, AL
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 beta-Smad2/3 signaling. Targeting the ubiquitous TGF beta 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 beta 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 beta RI-Hsp90 complex, resulting in a decrease in TGF beta 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 beta-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Datos de la publicación
- ISSN/ISSNe:
- 0022-2828, 1095-8584
- Tipo:
- Article
- Páginas:
- 75-87
- PubMed:
- 30193958
- Enlace a otro recurso:
- www.sciencedirect.com
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Citas Recibidas en Web of Science: 20
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Keywords
- Consensus tertratricopeptide repeat (CTPR); Designed proteins; Hsp90/ Hsp90 protein inhibitor; Myocardial fibrosis; TGF beta signaling
