Abstract | BACKGROUND: METHODS: In Experiment I (survival study), Wistar-Kyoto rats were subjected to HS (55% volume blood loss), followed by intraperitoneal injection of either Tub A (70 mg/kg) dissolved in dimethyl sulfoxide ( DMSO) or DMSO only (vehicle group) (n = 8 per group). Survival was monitored for 24 hours. In Experiment II (physiologic study), rats were subjected to a sublethal HS (40% blood loss), followed by the same treatment with Tub A (treatment group) or DMSO only (vehicle group, n = 5 per group). All animals were sacrificed 6 hours after hemorrhage, and the heart and liver tissues were harvested. Sham animals were not subjected to hemorrhage and treatment ( sham group, n = 5 per group). Cardiac mitochondria were isolated to study the pyruvate dehydrogenase (PDH, an essential enzyme for adenosine triphosphate production) activity. Liver tissue lysates were analyzed for markers of apoptosis ( cytochrome c, cleaved caspase 3) and inflammation (high-mobility group box 1) by Western blotting. RESULTS: Severe HS (55% blood loss) was associated with 75% mortality, which was significantly improved by Tub A treatment (37.5% mortality in 24 hours, p = 0.048). Tub A also significantly enhanced the cardiac PDH activity compared with the vehicle group, while suppressing the hepatic high-mobility group box 1 expression, cytochrome c release, and caspase 3 activation. CONCLUSION: Our study has demonstrated for the first time that selective inhibition of HDAC6 can improve survival in a rodent model of HS. The potential mechanisms include enhanced PDH activity, decreased inflammatory drive, and attenuated cellular apoptosis.
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Authors | Zhigang Chang, Yongqing Li, Wei He, Baoling Liu, Ihab Halaweish, Ted Bambakidis, Yingjian Liang, Hasan B Alam |
Journal | The journal of trauma and acute care surgery
(J Trauma Acute Care Surg)
Vol. 79
Issue 6
Pg. 905-10
(Dec 2015)
ISSN: 2163-0763 [Electronic] United States |
PMID | 26680133
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Biomarkers
- Histone Deacetylase Inhibitors
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Topics |
- Animals
- Apoptosis
- Biomarkers
(metabolism)
- Blotting, Western
- Disease Models, Animal
- Histone Deacetylase Inhibitors
(pharmacology)
- Male
- Rats
- Rats, Inbred WKY
- Shock, Hemorrhagic
(drug therapy)
- Survival Rate
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