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

Abstract

Hemorrhage is the leading cause of preventable trauma-related deaths. We have previously shown that treatment with Tubastatin A (Tub A), a histone deacetylase 6 (HDAC6) inhibitor, can improve survival in a rodent model of septic shock. The aims of the present study were to determine whether selective inhibition of HDAC6 can promote survival in a model of hemorrhagic shock (HS). 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. 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. 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.