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Título: | Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein |
Autor: | Cáceres, Rodrigo; Chavez, Tatiana; Maestro, David CSIC; Palanca, Ana R.; Bolado, Patricia; Madrazo, F.; Aires, Antonio; Cortajarena, Aitziber L. CSIC ORCID; Villar Ramos, Ana V. CSIC ORCID | Palabras clave: | Consensus tertratricopeptide repeat (CTPR) Designed proteins Hsp90/ Hsp90 protein inhibitor Myocardial fibrosis TGFβ signaling |
Fecha de publicación: | oct-2018 | Editor: | Academic Press Elsevier |
Citación: | Journal of Molecular and Cellular Cardiology 123: 75-87 (2018) | Resumen: | 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. | Versión del editor: | http://dx.doi.org/10.1016/j.yjmcc.2018.08.016 | URI: | http://hdl.handle.net/10261/249055 | DOI: | 10.1016/j.yjmcc.2018.08.016 | Identificadores: | doi: 10.1016/j.yjmcc.2018.08.016 issn: 0022-2828 |
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Reduction_Caceres_Postprint_Art2018.pdf | 1,31 MB | Adobe PDF | Visualizar/Abrir |
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