Identification of a Novel Potential Biomarker in a Model of Hemorrhagic Shock and Valproic Acid Treatment

Li, Yongqing; Liu, Baoling; Dillon, Simon T.; Fukudome, Eugene Y.; Kheirbek, Tareq; Sailhamer, Elizabeth A.; Velmahos, George C.; DeMoya, Marc; Libermann, Towia A.; Alam, Hasan B.

doi:10.1016/j.jss.2009.04.011

Cited by 23 publications

(22 citation statements)

References 19 publications

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“…Currently, there has been much focus on VPA because this agent has shown promise in cellular protection after periods of ischemia or hemorrhage, but these pathways are largely unknown. [23][24][25] Our results have identified factors related to apoptosis/ cell death and angiogenesis/vascular development as being among the major pharmacologic targets of VPA after a severe ischemia-reperfusion injury, particularly VEGF and TGF-␤. Although it is possible that changes in hemodynamic factors and other aspects of the injury contributed to the changes in gene expression in the VPA-treated animals, the genes we discovered that changed have been identified as transcriptional targets of VPA in several in vitro models.…”

Section: Discussionmentioning

confidence: 78%

Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia–reperfusion injury in a swine hemorrhagic shock model

Causey

Salgar

Singh

et al. 2012

Journal of Vascular Surgery

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Section: Discussionmentioning

confidence: 78%

Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia–reperfusion injury in a swine hemorrhagic shock model

Causey

Salgar

Singh

et al. 2012

Journal of Vascular Surgery

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“…Recent studies from our group (Li et al 2010) and others (Thuijls et al 2009) have shown that HS leads to destruction of the gut barrier due to TJ protein loss. Also it was found that the claudin-3 protein is released into circulation very early (30–60 min) after the onset of HS (Li et al 2010). Alternatively, CINC, a chemokine that promotes neutrophil chemotaxis, is significantly elevated in serum and lung tissue with increased myeloperoxidase (MPO) levels at 4 h after hemorrhage.…”

Section: Hdaci In Models Of Hemorrhagic Shockmentioning

confidence: 99%

“…Other HDACI such as TSA and SAHA have been shown to decrease LPS-induced inflammation in mice (Cao et al 2008; Li et al 2009; Li et al 2010). In RAW 264.7 cells, treatment of the macrophages with SAHA significantly suppresses LPS-induced gene expression and protein production of IL-1β, IL-6, and TNF-α (Li et al 2009; Li et al 2010). In an in vivo rodent model of septic shock, HDACI attenuate acute lung and liver injury, and improve survival (Zhang et al 2009; Li et al 2010; Zhang et al 2010).…”

Section: Hdaci In Models Of Septic Shockmentioning

confidence: 99%

“…Recently, our group has found that HDAC inhibitor SAHA can reduce the expression of MyD88 gene and protein in vitro and in vivo after LPS insult (Li et al 2010). Moreover, SAHA acetylates heat shock protein 90 (Hsp90) and de-associates the protein from IRAK1, resulting in IRAK1 degradation (Chong et al, unpublished data).…”

Section: Hdaci In Models Of Septic Shockmentioning

confidence: 99%

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Creating a Pro-survival and Anti-inflammatory Phenotype by Modulation of Acetylation in Models of Hemorrhagic and Septic Shock

Alam

2011

Advances in Experimental Medicine and Biology

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Shock, regardless of etiology, is characterized by decreased tissue perfusion resulting in cell death, organ dysfunction, and poor survival. Current therapies largely focus on restoring tissue perfusion through resuscitation but have failed to address the specific cellular dysfunction caused by shock. Acetylation is rapidly emerging as a key mechanism that regulates the expression of numerous genes (epigenetic modulation through activation of nuclear histone proteins), as well as functions of multiple cytoplasmic proteins involved in key cellular functions such as cell survival, repair/healing, signaling, and proliferation. Cellular acetylation can be increased immediately through the administration of histone deacetylase inhibitors (HDACI). A series of studies have been performed using: (1) cultured cells; (2) single-organ ischemia-reperfusion injury models; (3) rodent models of lethal septic and hemorrhagic shock; (4) swine models of lethal hemorrhagic shock and multi-organ trauma; and (5) tissues from severely injured trauma patients, to fully characterize the changes in acetylation that occur following lethal insults and in response to treatment with HDACI. These data demonstrate that: (1) shock causes a decrease in acetylation of nuclear and cytoplasmic proteins; (2) hypoacetylation can be rapidly reversed through the administration of HDACI; (3) normalization of acetylation prevents cell death, decreases inflammation, attenuates activation of pro-apoptotic pathways, and augments pro-survival pathways; (4) the effect of HDACI significantly improves survival in lethal models of septic shock, hemorrhagic shock, and complex poly-trauma without need for conventional fluid resuscitation or blood transfusion; and (5) improvement in survival is not due to better resuscitation but due to an enhanced ability of cells to tolerate lethal insults. As different models of hemorrhagic or septic shock have specific strengths and limitations, this chapter will summarize our attempts to create “pro-survival and anti-inflammatory phenotype” in various models of hemorrhagic shock and septic shock.

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“…10, 11 Hypoperfusion or ischemia can cause loss of TJs and disruption of the intestinal barrier integrity, which leads to increased permeability 5, 12 enhanced potential for bacterial translocation, systemic inflammation, and distant organ damage. 5, 13 Recent studies from our group 14 and others 5 have shown that HS leads to an impairment of the gut barrier due to the loss of TJ proteins. We have also shown that treatment with a pan-histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can stabilize the intestinal claudin-3, maintain the mucosal TJ integrity, and prevent harmful gut-derived substances from getting into the systemic circulation.…”

Section: Introductionmentioning

confidence: 98%

Inhibition of histone deacetylase 6 restores intestinal tight junction in hemorrhagic shock

Chang

et al. 2016

Journal of Trauma and Acute Care Surgery

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Background We recently discovered that Tubastatin-A, histone deacetylase (HDAC6) inhibitor, can improve survival in a rodent model of hemorrhagic shock (HS), but mechanisms remain poorly defined. In this study we investigated whether Tubastatin-A could protect intestinal tight junction (TJ) in HS. Methods In-vivo study: Wistar-Kyoto rats underwent HS (40% blood loss) followed by Tubastatin-A (70 mg/kg) treatment, without fluid resuscitation. The experimental groups were: (1) sham (no hemorrhage, no treatment), (2) control (hemorrhage, without treatment), and (3) treatment (hemorrhage with Tubastatin-A administration). Three hours after hemorrhage, ileum was harvested. Whole cell lysate were analyzed for acetylated α-tubulin (Ac-tubulin), total tubulin, acetylated histone 3 at lysine 9 (Ac-H3K9), β-actin, claudin-3 and zonula occludens 1 (ZO-1) proteins by western blot. Histological effects of Tubastatin-A on small bowel were examined. In-vitro study: human intestinal epithelial cells (Caco-2) were divided into 3 groups: (1) sham (normoxia), (2) control (anoxia, no treatment), (3) treatment (anoxia, treatment with Tubastatin-A). After 12 hours in a anoxia chamber, the cells were examined for Ac-tubulin and Ac-H3K9, cellular viability, cytotoxicity, claudin-3 and ZO-1 protein expression, and transwell permeability study. Results Tubastatin-A treatment significantly attenuated HS-induced decreases of Ac-tubulin, Ac-H3K9, ZO-1 and claudin-3 proteins in small bowel in-vivo (P<0.05). In cultured Caco-2 cells, anoxia significantly decreased cellular viability (P<0.001) and increased cytotoxicity (P<0.001) compared to the sham group, while Tubastatin-A treatment offered significant protection (P<0.0001). Moreover, expression of claudin-3 was markedly decreased in-vitro compared to the sham group, whereas this was significantly attenuated by Tubastatin-A (P<0.05). Finally, anoxia markedly increased the permeability of Caco-2 monolayer cells (P<0.05), while Tubastatin-A significantly attenuated the alteration (P<0.05). Conclusion Inhibition of HDAC6 can induce Ac-tubulin and Ac-H3K9, promote cellular viability, and prevent the loss of intestinal TJ proteins during HS and anoxia.

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Identification of a Novel Potential Biomarker in a Model of Hemorrhagic Shock and Valproic Acid Treatment

Cited by 23 publications

References 19 publications

Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia–reperfusion injury in a swine hemorrhagic shock model

Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia–reperfusion injury in a swine hemorrhagic shock model

Creating a Pro-survival and Anti-inflammatory Phenotype by Modulation of Acetylation in Models of Hemorrhagic and Septic Shock

Inhibition of histone deacetylase 6 restores intestinal tight junction in hemorrhagic shock

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