Abstract
Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histone and nonhistone proteins and in regulating fundamental cellular activities. In this paper we review and discuss intriguing recent developments in the use of histone deacetylase inhibitors (HDACIs) to combat some critical conditions in an animal model of hemorrhagic and septic shock. HDACIs have neuroprotective, cardioprotective, renal-protective, and anti-inflammatory properties; survival improvements have been significantly shown in these models. We discuss the targets and mechanisms underlying these effects of HDACIs and comment on the potential new clinical applications for these agents in the future. This paper highlights the emerging roles of HDACIs as acetylation modulators in models of hemorrhagic and septic shock and explains some contradictions encountered in previous studies.
Highlights
Hemorrhagic shock (HS) is a major cause of morbidity and mortality among trauma patients
Gao and Newton showed that heat-shock protein 70 (Hsp70) directly binds and stabilizes Akt/PKB as well as protein kinase A and protein kinase C, prolonging the signaling lifetime of the kinases [75]. These findings suggest that the Phosphoinositide 3-Kinase (PI3K)/Akt pathway and Sp1 are likely involved in Hsp70 induction by histone deacetylase inhibitors (HDACIs), and this induction may in turn interact with Akt/PKB to sustain the active state of Akt to protect the cells from apoptosis
We recently demonstrated that sublethal hemorrhagic shock (40% blood loss) results in phosphorylation of extracellular signal-regulated kinase (ERK), Jun Nterminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in lung tissues at 1 and 4 hours compared to the sham group
Summary
Hemorrhagic shock (HS) is a major cause of morbidity and mortality among trauma patients. Class III HDACs are referred to as sirtuins owing to their homology to the yeast HDAC Sir2 This class includes SIRT1–SIRT7 [9, 10]. Many of them are broad-spectrum- or pan-HDACIs which inhibit many of the Class I, II, and IV isoforms, including suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), and valproic acid (VPA) Some clinical compounds such as MS-275, FK-228, and apicidin have been termed as “Class I-selective”, since they target several Class I isoforms of HDAC. Protein concentration and enzyme activity of HAT and HDAC remain in a highly harmonized state of balance, which is named as “acetylation homeostasis” to emphasize the importance of regulated acetylation in acceding cellular homeostasis [20]. This paper highlights the emerging roles of HDACIs as acetylation modulators in models of hemorrhagic shock and septic shock, and explains some contradictions encountered in previously published results
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