BACKGROUND: We have demonstrated that valproic acid (VPA), a histone deacetylase inhibitor (HDACI), can improve animal survival after hemorrhagic shock, and protect neurons from hypoxia-induced apoptosis. This study investigated whether VPA treatment works through the c-Jun N-terminal kinase (JNK)/Caspase-3 survival pathways. METHODS: Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss over 60 min) followed by post-shock treatment with VPA (300 mg/kg), without any additional resuscitation fluids. The experimental groups were: (1) Sham (no hemorrhage, no resuscitation), (2) no resuscitation (hemorrhage, no resuscitation), and (3) VPA treatment. The animals were sacrificed at 1, 6, or 24h (n=3/timepoint), and liver tissue was harvested. Cytosolic and nuclear proteins were isolated and analyzed for acetylated histone-H3 at lysine-9 (Ac-H3K9), total and phosphorylated JNK, and activated caspase-3 by Western blot. RESULTS: Hemorrhaged animals were in severe shock, with mean arterial pressures of 25-30 mmHg and lactic acid 7-9 mg/dL. As expected, only the VPA treated animals survived to the 6- and 24-h timepoints; none of the non-resuscitated animals survived to these time points. Treatment of hemorrhaged animals with VPA induced acetylation of histone H3K9, which peaked at 1h and returned back to normal by 24h. Hemorrhage induced phosphorylation of JNK (active form) and increased activated caspase-3 levels, representing a commitment to subsequent cell death. Treatment with VPA decreased the phospho-JNK (P=0.06) expression at 24h, without changing the total levels of JNK (P=0.89), and this correlated with attenuation of activated caspase-3 at 24h (P=0.04), compared with the non-resuscitated animals. CONCLUSION: Treatment with HDACI, induces acetylation of histone H3K9, and reduces JNK phosphorylation and subsequent caspase-3 activation. This discovery establishes for the first time that HDACI may protect cells after severe hemorrhage through modulation of the JNK/caspase-3 apoptotic pathway.
BACKGROUND: We have demonstrated that valproic acid (VPA), a histone deacetylase inhibitor (HDACI), can improve animal survival after hemorrhagic shock, and protect neurons from hypoxia-induced apoptosis. This study investigated whether VPA treatment works through the c-Jun N-terminal kinase (JNK)/Caspase-3 survival pathways. METHODS: Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss over 60 min) followed by post-shock treatment with VPA (300 mg/kg), without any additional resuscitation fluids. The experimental groups were: (1) Sham (no hemorrhage, no resuscitation), (2) no resuscitation (hemorrhage, no resuscitation), and (3) VPA treatment. The animals were sacrificed at 1, 6, or 24h (n=3/timepoint), and liver tissue was harvested. Cytosolic and nuclear proteins were isolated and analyzed for acetylated histone-H3 at lysine-9 (Ac-H3K9), total and phosphorylated JNK, and activated caspase-3 by Western blot. RESULTS:Hemorrhaged animals were in severe shock, with mean arterial pressures of 25-30 mmHg and lactic acid 7-9 mg/dL. As expected, only the VPA treated animals survived to the 6- and 24-h timepoints; none of the non-resuscitated animals survived to these time points. Treatment of hemorrhaged animals with VPA induced acetylation of histone H3K9, which peaked at 1h and returned back to normal by 24h. Hemorrhage induced phosphorylation of JNK (active form) and increased activated caspase-3 levels, representing a commitment to subsequent cell death. Treatment with VPA decreased the phospho-JNK (P=0.06) expression at 24h, without changing the total levels of JNK (P=0.89), and this correlated with attenuation of activated caspase-3 at 24h (P=0.04), compared with the non-resuscitated animals. CONCLUSION: Treatment with HDACI, induces acetylation of histone H3K9, and reduces JNK phosphorylation and subsequent caspase-3 activation. This discovery establishes for the first time that HDACI may protect cells after severe hemorrhage through modulation of the JNK/caspase-3 apoptotic pathway.
Authors: Frederick W Damen; Amelia R Adelsperger; Katherine E Wilson; Craig J Goergen Journal: J Am Assoc Lab Anim Sci Date: 2015-11 Impact factor: 1.232
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Authors: Panpan Chang; Michael Weykamp; Isabel S Dennahy; Aaron M Williams; Umar F Bhatti; Baoling Liu; Vahagn C Nikolian; Yongqing Li; Hasan B Alam Journal: J Trauma Acute Care Surg Date: 2018-05 Impact factor: 3.313
Authors: Eugene Y Fukudome; Ashley R Kochanek; Yongqing Li; Eleanor J Smith; Baoling Liu; Tareq Kheirbek; Jennifer Lu; Kyuseok Kim; Kristopher Hamwi; George C Velmahos; Hasan B Alam Journal: J Surg Res Date: 2010-05-07 Impact factor: 2.192
Authors: Aaron M Williams; Isabel S Dennahy; Umar F Bhatti; Ben E Biesterveld; Nathan J Graham; Yongqing Li; Hasan B Alam Journal: Shock Date: 2019-09 Impact factor: 3.454