HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions.

Jinyan Yu,Jian Fu,Zhongsen Ma,Mengshi Ma

doi:10.18632/oncotarget.10591

Jinyan Yu, Jian Fu + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.10591

Copy DOI

Journal: Oncotarget	Publication Date: Jul 13, 2016
Citations: 57	License type: cc-by

Affiliation: Jilin University, University of Kentucky

Abstract

Pro-inflammatory mediators such as TNF-α induce caspase activation in endothelial cells, which leads to degradation of cellular proteins, induction of apoptotic signaling, and endothelial cell dysfunction. New therapeutic agents that can inhibit caspase activation may provide protection against inflammatory injury to endothelial cells. In the present study, we examined the effects of selective histone deacetylase 6 (HDAC6) inhibition on TNF-α induced caspase 3 activation and cell-cell junction dysfunction in lung endothelial cells. We also assessed the protective effects of HDAC6 inhibition against lung inflammatory injury in a mouse model of endotoxemia. We demonstrated that selective HDAC6 inhibition or knockdown of HDAC6 expression was able to prevent caspase 3 activation in lung endothelial cells and maintain lung endothelial cell-cell junctions. Mice pre-treated with HDAC6 inhibitors exhibited decreased endotoxin-induced caspase 3 activation and reduced lung vascular injury as indicated by the retention of cell-cell junction protein VE-Cadherin level and alleviated lung edema. Collectively, our data suggest that HDAC6 inhibition is a potent therapeutic strategy against inflammatory injury to endothelial cells.

Highlights

Inflammation-mediated endothelial cell damage including inflammatory lung vascular injury is often associated with caspase activation and endothelial cell barrier dysfunction [1]
We examined the effects of selective histone deacetylase 6 (HDAC6) inhibition on tumor necrosis factor (TNF)-α induced caspase 3 activation and cell-cell junction dysfunction in lung endothelial cells
We first assessed whether HDAC6 inhibition can block caspase-3 activation in lung endothelial cells

Summary

Introduction

Inflammation-mediated endothelial cell damage including inflammatory lung vascular injury is often associated with caspase activation and endothelial cell barrier dysfunction [1]. Over-production of proinflammatory mediators such as tumor necrosis factor (TNF)-α is a major cause of endothelial cell injury during inflammation [1]. Tumor necrosis factor (TNF)-α-induced caspase activation and endothelial cell dysfunction contribute to inflammatory vascular injury in endotoxemia and sepsis [1]. Caspase-3 activation plays an important role in endothelial cell barrier dysfunction as a result of apoptotic signaling and re-organization of cell-cell junction proteins including ZO-1 and VE-Cadherin [2,3,4]. TNF-α induces endothelial barrier disruption by dis-organization of microtubule, actin cytoskeleton and cell junctions [6,7,8,9]

Methods

Results

Conclusion