Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis

Vilatobá, Mario; Eckstein, Christopher; Bilbao, Guadalupe; Smyth, Cheryl A.; Jenkins, Stacie; Thompson, John A.; Eckhoff, Devin E.; Contreras, Juan L.

doi:10.1016/j.surg.2005.04.019

Cited by 137 publications

(120 citation statements)

References 45 publications

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“…4-PBA is a low molecular weight compound that stabilizes protein conformation, improves folding capacity of the ER and facilitates trafficking of mutant proteins. 31 4-PBA has been demonstrated to reduce the load of mutant or mislocated proteins retained in the ER under conditions associated with cystic fibrosis and liver injury. 25 It is also reported that 4-PBA has a neuroprotective effect on cerebral ischemic injury in a mouse model of ischemia/hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Sawada

Yao

Hiramatsu

et al. 2008

Laboratory Investigation

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In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl 2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl 2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.

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Section: Discussionmentioning

confidence: 99%

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Sawada

Yao

Hiramatsu

et al. 2008

Laboratory Investigation

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“…PBA has multiple biological activities, including as HDAC inhibition [28], chemical chaperoning upon endoplasmic reticulum (ER) stress [38,39], ammonia scavenging in urea cycle dysfunction [31,32]. Urea cycle dysfunction in heart has never been reported after decades of intensive research of ADR cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Daosukho

Chen

Noel

et al. 2007

Free Radical Biology and Medicine

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Cardiac injury is a major complication for oxidative stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected one day before and daily after the ADR injection for two days. We found that PBA significantly decreased the ADR-associated elevation of serum lactase dehydrogenase (LDH) and creatine kinase (CK) activities, and diminished ADR-induced ultrastructual damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac MnSOD protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury, and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity.

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“…In order to confirm the correlation between apoptosis and the activation of ERS/UPR caused by cholesterol loading in hepatic L02 cells, UPR inhibitor PBA was used to treat cells and then the effects on the apoptotic cell death by cholesterol overloading was observed. PBA, a low-molecule-weight chaperone, stabilizes protein conformation, improves ER folding capacity, and inhibits lipid-induced ERS (37,38), but does not affect cellular lipid contents (13). Moreover, data indicate that the chemical chaperone PBA prevents cell death caused by hypoxia-induced ERS while decreasing CHOP expression (37,39).…”

Section: Discussionmentioning

confidence: 99%

“…PBA, a low-molecule-weight chaperone, stabilizes protein conformation, improves ER folding capacity, and inhibits lipid-induced ERS (37,38), but does not affect cellular lipid contents (13). Moreover, data indicate that the chemical chaperone PBA prevents cell death caused by hypoxia-induced ERS while decreasing CHOP expression (37,39). Thus, PBA typically acts as an inhibitor of UPR.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response

Liu²,

Guo³

et al. 2009

Int J Mol Med

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Abstract.Reported data indicate that cholesterol loading in the liver can cause hepatic injury. To explore the possible mechanisms of cell damage resulting from cholesterol overloading in hepatocytes, cell apoptosis, the unfolded protein response (UPR) and the correlation between them were assessed in the cholesterol-overloaded normal human hepatic cell line L02. L02 cells were incubated with 200 μg/ ml of low density lipoprotein (LDL) for 24 h with or without 20 μg/ml 58035, an inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). In the LDL+58035 group, the intracellular cholesterol level was dramatically increased, which was measured by an enzymatic combined high performance liquid chromatography assay. Expression of immunoglobulin-binding protein, X-box binding protein 1, activating transcription factor 6, activating transcription factor 4, CCAAT/enhancer-binding protein homologous protein-10, markers of endoplasmic reticulum stress (ERS)/ UPR, were up-regulated as determined using reverse transcription-polymerase chain reaction (RT-PCR) or Western blot analysis. The rate of cell apoptic death increased 21.3±2.4%. Meanwhile, the active caspase-3 protein expression was increased 8.4-fold compared to the active caspase-3 protein expression in the controls. Furthermore, 4-phenylbutyric acid, an inhibitor of UPR, partly reduced cell apoptosis and activation of caspase-3. This study suggests that cholesterol overloading in hepatic L02 cells induces ERS and activates the UPR which, in part, leads to the apoptotic damage of cells.

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Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis

Cited by 137 publications

References 45 publications

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response

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