A COMPARATIVE ANALYSIS TO DETERMINE THE OPTIMUM HISTONE DEACETYLASE INHIBITORS AND ADMINISTRATION ROUTE FOR IMPROVING SURVIVAL AND ORGAN INJURY IN RATS AFTER HEMORRHAGIC SHOCK

ABSTRACT Objective: Histone deacetylase inhibitors (HDACIs) have been reported to improve survival in rats with hemorrhagic shock (HS). However, no consensus exists on the most effective HDACIs and their administration routes. We herein aimed to determine the optimal HDACIs and administration route in rats with HS. Methods: Survival analysis: In experiment I, male Sprague-Dawley rats were subjected to HS (mean arterial pressure [MAP] was maintained at 30–40 mm Hg for 20 min), and intravenously injected with the following agents (n = 8 per group): (1) no treatment, (2) vehicle (VEH), (3) entinostat (MS-275), (4) [N-((6-(Hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide] (LMK-235), (5) tubastatin A, (6) trichostatin A (TSA), and (7) sirtinol. In experiment II, rats were intraperitoneally injected with TSA. Mechanism research: In experiments I and II, rats were observed for 3 h, after which blood samples and liver, heart, and lung tissues were harvested. Results: In experiment I, 75% rats in the VEH group but only 25% rats in the LMK-235 and sirtinol groups died within ≤5 h of treatment, whereas the survival of rats in the MS-275, tubastatin A, and TSA groups was significantly prolonged. MS-275, LMK-235, tubastatin A, and TSA significantly reduced histopathological scores, apoptosis cell numbers, and inflammatory cytokine levels. In experiment II, the survival was longer after i.v. TSA treatment than after i.p. TSA treatment, and the IL-6 levels in the heart were significantly lower in rat who received i.p. TSA treatment than in those who received i.v. TSA treatment. Conclusions: The i.v. effect was superior to the i.p. effect, while nonselective and isoform-specific classes I and IIb HDACIs had similar effects.

[1]  E. Vicaut,et al.  Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock , 2021, Frontiers in Immunology.

[2]  Xiang-min Yang,et al.  Wogonin alleviates liver injury in sepsis through Nrf2‐mediated NF‐κB signalling suppression , 2021, Journal of cellular and molecular medicine.

[3]  Huilin Li,et al.  Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs) , 2020, International journal of molecular sciences.

[4]  Joseph M. Galante,et al.  AAST - WSES Guidelines on Diagnosis and Management of Abdominal Vascular Injuries. , 2020, The journal of trauma and acute care surgery.

[5]  K. Matsushima,et al.  The use of warm fresh whole blood transfusion in the austere setting: A civilian trauma experience , 2020, The journal of trauma and acute care surgery.

[6]  Weiyang Shen,et al.  JLX001 improves myocardial ischemia-reperfusion injury by activating Jak2-Stat3 pathway. , 2020, Life sciences.

[7]  B. Shenkman,et al.  Differences in the Role of HDACs 4 and 5 in the Modulation of Processes Regulating MAFbx and MuRF1 Expression during Muscle Unloading , 2020, International journal of molecular sciences.

[8]  Alexander T. Williams,et al.  Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin , 2020, Scientific Reports.

[9]  Xiaobo Yang,et al.  Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis. , 2019, International immunopharmacology.

[10]  Zhongmin Yuan,et al.  Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 , 2019, Front. Cell. Neurosci..

[11]  Aaron M Williams,et al.  Comparative analysis of isoform-specific and non-selective histone deacetylase inhibitors in attenuating the intestinal damage after hemorrhagic shock , 2019, Trauma Surgery & Acute Care Open.

[12]  Nathan J. Graham,et al.  Histone Deacetylase Inhibitors: A Novel Strategy In Trauma And Sepsis. , 2019, Shock.

[13]  Myung Ho Jeong,et al.  Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertension , 2019, PloS one.

[14]  M. Jeong,et al.  Histone deacetylase inhibitor LMK235 attenuates vascular constriction and aortic remodelling in hypertension , 2019, Journal of cellular and molecular medicine.

[15]  S. Di,et al.  Icariin protects cardiomyocytes against ischaemia/reperfusion injury by attenuating sirtuin 1‐dependent mitochondrial oxidative damage , 2018, British journal of pharmacology.

[16]  Aaron M Williams,et al.  Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model , 2018, The journal of trauma and acute care surgery.

[17]  S. Cimbanassi,et al.  Evaluation of capillary leakage after vasopressin resuscitation in a hemorrhagic shock model , 2018, World Journal of Emergency Surgery.

[18]  F. Sheppard,et al.  Whole blood and Hextend: Bookends of modern tactical combat casualty care field resuscitation and starting point for multifunctional resuscitation fluid development , 2017, The journal of trauma and acute care surgery.

[19]  H. Masumoto,et al.  Fetal mesenchymal stem cells ameliorate acute lung injury in a rat cardiopulmonary bypass model , 2017, The Journal of thoracic and cardiovascular surgery.

[20]  H. Masumoto,et al.  Recombinant human soluble thrombomodulin prevents acute lung injury in a rat cardiopulmonary bypass model , 2017, Journal of Thoracic and Cardiovascular Surgery.

[21]  H. Alam,et al.  Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock , 2015, The journal of trauma and acute care surgery.

[22]  S. Dupré-Aucouturier,et al.  Trichostatin A, a histone deacetylase inhibitor, modulates unloaded-induced skeletal muscle atrophy. , 2015, Journal of applied physiology.

[23]  H. Alam,et al.  Hypothermia and valproic acid activate prosurvival pathways after hemorrhage. , 2015, The Journal of surgical research.

[24]  Huang-Ping Yu,et al.  Sirtinol attenuates trauma hemorrhage–induced hepatic injury through Akt-dependent pathway in rats , 2013, The journal of trauma and acute care surgery.

[25]  Travis P. Webb.  Diagnosis and management of abdominal vascular injuries , 2013 .

[26]  J. Davie,et al.  Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors , 2012, Clinical Epigenetics.

[27]  E. Mizutani,et al.  Inhibition of Class IIb Histone Deacetylase Significantly Improves Cloning Efficiency in Mice1 , 2010, Biology of reproduction.

[28]  Sheng-wei Jin,et al.  Histone Deacetylase Inhibitors Attenuate Acute Lung Injury During Cecal Ligation and Puncture-Induced Polymicrobial Sepsis , 2010, World Journal of Surgery.

[29]  O. Witt,et al.  HDAC family: What are the cancer relevant targets? , 2009, Cancer letters.

[30]  P. Rhee,et al.  Searching for the optimal resuscitation method: recommendations for the initial fluid resuscitation of combat casualties. , 2003, The Journal of trauma.

[31]  D. Spain,et al.  A multicenter evaluation of whether gender dimorphism affects survival after trauma. , 2001, American journal of surgery.

[32]  Xiaoyang Li,et al.  Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics , 2018, Advances in cancer research.

[33]  J. Holcomb,et al.  Optimal Fluid Therapy for Traumatic Hemorrhagic Shock. , 2017, Critical care clinics.

[34]  Jae Kwon Lee,et al.  Histone deacetylase inhibitors decrease the antigen presenting activity of murine bone marrow derived dendritic cells. , 2010, Cellular immunology.

[35]  M D Blaufox,et al.  Blood volume in the rat. , 1985, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.