Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock

Chang, Zhigang; Li, Yongqing; He, Wei; Liu, Baoling; Halaweish, Ihab; Bambakidis, Ted; Liang, Yingjian; Alam, Hasan B.

doi:10.1097/ta.0000000000000784

Cited by 15 publications

(23 citation statements)

References 42 publications

(46 reference statements)

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“…HDAC6 inhibition resulted in prolonged survival in murine models of hemorrhagic shock and sepsis (8,10,28). However, molecular mechanisms of the protective effects observed by HDAC6 inhibition in those models have yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

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Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

Shetty

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

“…Tubastatin A is the most effective HDAC6 inhibitor available so far. Tubastatin A has been reported to reduce stress responses and prolong survival in lethal sepsis models (10, 28, 52-54), and tubastatin A also possesses anti-inflammatory, antirheumatic, and neuroprotective effects (8,11,25,45).…”

mentioning

confidence: 99%

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

Shetty

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Tubastatin A has been reported to possess anti-inflammatory effects [20–23]. Tubastatin A treatment can prevent stress responses and prolong survival during systemic inflammation [24–28].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

Oncotarget

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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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“…An acetyl group can be added to a lysine residue by histone acetyl transferases (HATs) and removed by histone deacetylases (HDACs). Based on their structure and homology to yeast histone deacetylases, HDACs are classified into four classes: class I HDACs (HDAC1, 2, 3, and 8); class II HDACs (HDAC4, 5, 6, 7, 9, and 10); class III HDACs (SIRT1-7); and class IV (HDAC11) (8,9). HDACs have been shown to be associated with many cell functions including cell growth, dedifferentiation, and proliferation and apoptosis (24,41) and have become a target for drug development to treat cancer, including acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, and breast cancer (43).…”

mentioning

confidence: 99%

“…Increasing evidence has indicated that the function of HDAC6 is not limited to tumorgenesis but also implicated in some chronic diseases such as neurodegenerative diseases, cardiovascular disease, fibrosis, and cystogenesis (3,4,8,11,51). Interestingly, recent studies have shown that HDAC6 activation is also associated with pathogenesis of acute organ/ tissue injury (9,25,38,46). For example, postischemic treat- ment with tubastatin A (TA), a highly selective HDAC6 inhibitor, improved functional recovery, reduced brain infarct volume, and ameliorated neuronal cell death in a rat model of transient middle cerebral artery occlusion (38).…”

mentioning

confidence: 99%

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

Shi

Tang

et al. 2017

American Journal of Physiology-Renal Physiology

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Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.

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Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock

Cited by 15 publications

References 42 publications

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

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

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

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