Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model

Chang, Pao‐Li; Weykamp, Michael; Dennahy, Isabel S.; Williams, Aaron M.; Bhatti, Umar F.; Liu, Baoling; Nikolian, Vahagn C.; Li, Yongqing; Alam, Hasan B.

doi:10.1097/ta.0000000000001824

Cited by 24 publications

(14 citation statements)

References 47 publications

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“…72,73 Considering the distinct tissue distribution and cellular localization of individual HDACs, as well as the relationship between specic HDAC isoforms and different kinds of cancers, researchers hypothesized isoform-selective HDACis may possess better therapeutic index and fewer adverse effects. [74][75][76] However, the therapeutic advantages of isoform-selective HDACis have not yet been proved clinically, and are still in course of studies. 77,78…”

Section: Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

et al. 2019

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Section: Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

et al. 2019

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“…In the present study, we established a 40% fixed-blood-loss HS rat model ( Chang et al, 2018 ) and interestingly, we found that 12 h of hemorrhagic shock caused damage to the rat myocardial mitochondrial structure, increased mtDNA release and ROS content, activated the mitochondrial and ROS-related pathways and indeced the systemic inflammatory response. We applied SkQ1 in HS treatment for the first time in this study and found that SkQ1 could reduce inflammation following hemorrhagic shock by protecting myocardial mitochondria.…”

Section: Introductionmentioning

confidence: 67%

Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria

Jia

Gan

et al. 2022

Front. Physiol.

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Background: Hemorrhagic shock (HS) is a type of hypovolemic shock characterized by hemodynamic instability, tissue hypoperfusion and cellular hypoxia. In pathophysiology, the gradual accumulation of reactive oxygen species (ROS) damages the mitochondria, leading to irreversible cell damage and the release of endogenous damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (MTDs), eventually triggering the inflammatory response. The novel mitochondria-targeted antioxidant SkQ1 (Visomitin) effectively eliminate excessive intracellular ROS and exhibits anti-inflammatory effects; however, the specific role of SkQ1 in HS has not yet been explicated.Methods and results: A 40% fixed-blood-loss HS rat model was established in this study. Transmission electron microscopy showed that after HS, the myocardial mitochondrial ultrastructure was damaged and the mtDNA release in circulation was increased and the differentially expressed genes were significantly enriched in mitochondrial and ROS-related pathways. Mitochondria-targeted antioxidant SkQ1 attenuated the increased ROS induced by HS in myocardial tissues and by oxygen-glucose deprivation (OGD) in cardiomyocytes. Ultrastructurally, SkQ1 protected the myocardial mitochondrial structure and reduced the release of the peripheral blood mtDNA after HS. RNA-seq transcriptome analysis showed that 56.5% of the inflammation-related genes, which altered after HS, could be significantly reversed after SkQ1 treatment. Moreover, ELISA indicated that SkQ1 significantly reversed the HS-induced increases in the TNF-α, IL-6, and MCP-1 protein levels in rat peripheral blood.Conclusion: HS causes damage to the rat myocardial mitochondrial structure, increases mtDNA release and ROS contents, activates the mitochondrial and ROS-related pathways, and induces systemic inflammatory response. The mitochondrial antioxidant SkQ1 can improve rat myocardial mitochondria ultrastructure, reduce mtDNA and ROS contents, and decrease inflammation by protecting myocardial mitochondria, thereby playing a novel protective role in HS.

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“…Despite the small samples, differences in survival were found, although the differences among sirtinol, MS-275, LMK-235, tubastatin A, and TSA treatments were not significant. Second, only male rats were used in this study, but this was because there is gender dimorphism in trauma patients (5,9,34), and female sex hormones are considered protective in shock. Future research will need to validate the effect of various HDACIs in female animals.…”

Section: Discussionmentioning

confidence: 99%

A Comparative Analysis to Determine the Optimum Histone Deacetylase Inhibitors and Administration Route for Improving Survival and Organ Injury in Rats After Hemorrhagic Shock

Niu¹,

Yang²,

Song³

et al. 2023

Shock

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Histone deacetylase inhibitors (HDACIs) have been reported to improve survival in rats with hemorrhagic shock (HS). However, no consensus exists on the most effective HDACIs and their administration routes. We herein aimed to determine the optimal HDACIs and administration route in rats with HS. Methods: Survival analysis: In experiment I, male Sprague-Dawley rats were subjected to HS (mean arterial pressure [MAP] was maintained at 30-40 mm Hg for 20 min), and intravenously injected with the following agents (n = 8 per group): (1) no treatment, (2) vehicle (VEH), ( 3) entinostat (MS-275), (4) [N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide] (LMK-235), (5) tubastatin A, (6) trichostatin A (TSA), and (7) sirtinol. In experiment II, rats were intraperitoneally injected with TSA. Mechanism research: In experiments I and II, rats were observed for 3 h, after which blood samples and liver, heart, and lung tissues were harvested. Results: In experiment I, 75% rats in the VEH group but only 25% rats in the LMK-235 and sirtinol groups died within ≤5 h of treatment, whereas the survival of rats in the MS-275, tubastatin A, and TSA groups was significantly prolonged. MS-275, LMK-235, tubastatin A, and TSA significantly reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels. In experiment II, the survival was longer after i.v. TSA treatment than after i.p. TSA treatment, and the IL-6 levels in the heart were significantly lower in rat who received i.p. TSA treatment than in those who received i.v. TSA treatment. Conclusions: The i.v. effect was superior to the i.p. effect, while nonselective and isoform-specific classes I and IIb HDACIs had similar effects.

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Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model

Abstract: Inhibition of HDAC classes IIa or IIb, but not class I, activates prosurvival pathways, which may be responsible for the improved outcomes in rodent models of HS.

Cited by 24 publications

References 47 publications

Next-generation of selective histone deacetylase inhibitors

Next-generation of selective histone deacetylase inhibitors

Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria

A Comparative Analysis to Determine the Optimum Histone Deacetylase Inhibitors and Administration Route for Improving Survival and Organ Injury in Rats After Hemorrhagic Shock

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