Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock

被引:51
作者
Gonzales, Earl R. [1 ]
Chen, Huazhen [1 ]
Munuve, Richard M. [1 ]
Mehrani, Tina [1 ]
Nadel, Amal [1 ]
Koustova, Elena [1 ]
机构
[1] Uniformed Serv Univ Hlth Sci, Dept Surg, Trauma Res & Readiness Inst Surg, Bethesda, MD 20814 USA
来源
JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE | 2008年 / 65卷 / 03期
关键词
valproate; hemorrhage; histone deacetylase; hyperacetylation; survival;
D O I
10.1097/TA.0b013e31818233ef
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Background: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of de-regulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation. Methods: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed. Results: VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished. Conclusion: VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.
引用
收藏
页码:554 / 564
页数:11
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