HDAC6 inhibition prevents TNF-α-induced caspase 3 activation in lung endothelial cell and maintains cell-cell junctions
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Jinyan Yu1,2,3, Mengshi Ma1,2, Zhongsen Ma1, Jian Fu2,3
1Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China
2Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY, USA
3Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, USA
Jian Fu, email: email@example.com
Zhongsen Ma, email: firstname.lastname@example.org
Keywords: caspase, endothelial, HDAC6, barrier function, inflammation
Received: May 05, 2016 Accepted: June 30, 2016 Published: July 13, 2016
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.
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