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Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Authors :
Carlos Hermenegildo
Carlos Bueno-Betí
Carmen Aguado
Susana Novella
Federico V. Pallardó
Daniel Pérez-Cremades
Carlos Romá-Mateo
Eva García-López
José Santiago Ibáñez-Cabellos
José Luis García-Giménez
Source :
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, r-CIPF: Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF), Centro de Investigación Principe Felipe (CIPF), Ibáñez Cabellos, Jose Santiago Aguado, Carmen Pérez Cremades, Daniel García-Giménez, Jose Luis Bueno Betí, Carlos García-López, Eva M. Romá-Mateo, Carlos Novella, Susana Hermenegildo, Carlos Pallardó, Federico V. 2018 Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells Biochimica et Biophysica Acta-Molecular Basis of Disease 1864 3234 3246, RODERIC. Repositorio Institucional de la Universitat de Valéncia, instname, r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF), r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
Publication Year :
2018

Abstract

Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage.

Details

ISSN :
1879260X and 09254439
Volume :
1864
Issue :
10
Database :
OpenAIRE
Journal :
Biochimica et biophysica acta. Molecular basis of disease
Accession number :
edsair.doi.dedup.....29866c2f2d8671f0031f4d5febcabfc3