Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

Department of Chemistry Faculty of Science University of Hradec Králové Hradec Králové Czechia

Department of Experimental Toxicology and Pharmacology National Poison Control Center Military Medical Academy Belgrade Serbia

Department of Neurology Charles University Prague Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Czechia

Department of Pharmacology Toxicology and Clinical Pharmacology Faculty of Medicine University of Banja Luka Banja Luka Bosnia and Herzegovina

Institute of Pathology University Clinical Center of Republic of Srpska Faculty of Medicine University of Banja Luka Banja Luka Bosnia and Herzegovina

Malaysia Japan International Institute of Technology Universiti Teknologi Malaysia Kuala Lumpur Malaysia

Medical Faculty of the Military Medical Academy University of Defense in Belgrade Belgrade Serbia

Zobrazit více v PubMed

Altieri D. C. (2010). Survivin and IAP proteins in cell-death mechanisms. PubMed DOI PMC

Andersson K. M., Brisslert M., Cavallini N. F., Svensson M. N., Welin A., Erlandsson M. C., et al. (2015). Survivin co-ordinates formation of follicular T-cells acting in synergy with Bcl-6. PubMed PMC

Bo L., Zhu X. S., Zheng Z., Hu X. P., Chen P. Y. (2017). Research on the function and mechanism of survivin in heart failure mice model. PubMed

Buerke U., Carter J. M., Schlitt A., Russ M., Schmidt H., Sibelius U., et al. (2008). Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. PubMed

Chang K. C., Unsinger J., Davis C. G., Schwulst S. J., Muenzer J. T., Strasser A., et al. (2007). Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis. PubMed DOI

Choi A. M., Ryter S. W., Levine B. (2013). Autophagy in human health and disease. PubMed DOI

Cohen J., Opal S., Calandra T. (2012). Sepsis studies need a new direction. PubMed DOI

Cui X., Shen D., Kong C., Zhang Z., Zeng Y., Lin X., et al. (2017). NF-κB suppresses apoptosis, and promotes bladder cancer cell proliferation by upregulating survivin expression in vitro, and in vivo. PubMed DOI PMC

Gravina G., Wasén C., Garcia-Bonete M. J., Turkkila M., Erlandsson M. C., Silversward S. T., et al. (2017). Survivinin autoimmune diseases. PubMed DOI

Hattori Y., Takano K., Teramae H., Yamamoto S., Yokoo H., Matsuda N. (2010). Insights into sepsis therapeutic design based on the apoptotic death pathway. PubMed DOI

Hotchkiss R. S., Monneret G., Payen D. (2013). Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. PubMed DOI PMC

Huang N., Wang F., Wang Y., Hou J., Li J., Deng X. (2013). Ulinastatin improves survival of septic mice by suppressing the inflammatory response and lymphocyte apoptosis. PubMed DOI

Jaćević V., Djordjevic A., Srdjenovic B., Milic-Tores V., Segrt Z., Dragojevic-Simic V., et al. (2017). Fullerenol nanoparticles prevent doxorubicin-induced acute hepatotoxicity in rats. PubMed DOI

Jaćević V., Dragojević-Simić V., Tatomirović Ž, Dobrić S., Bokonjić D., Kovačević A., et al. (2018). The efficacy of amifostine against multiple-dose doxorubicin-induced toxicity in rats. PubMed DOI PMC

Jaćević V., Jovic D., Kuca K., Dragojevic-Simic V., Dobric S., Trajkovic S., et al. (2016). Effects of fullerenol nanoparticles and amifostine on radiation-induced tissue damages: histopathological analysis. DOI

Koçkara A., Kayataş M. (2013). Renal cell apoptosis and new treatment options in sepsis-induced acute kidney injury. PubMed DOI

La Mura V., Pasarín M., Meireles C. Z., Miquel R., Rodríguez-Vilarrupla A., Hide D., et al. (2013). Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. PubMed DOI

Lee B. S., Oh J., Kang S. K., Park S., Lee S. H., Choi D., et al. (2015). Insulin protects cardiac myocytes from doxorubicin toxicity by sp1-mediated transactivation of survivin. PubMed DOI PMC

Liu X., Li B., Wang W., Zhang C., Zhang M., Zhang Y., et al. (2012). Effects of HMG-CoA reductase inhibitor on experimental autoimmune myocarditis. PubMed DOI

Marconi G. D., Zara S., De Colli M, Di Valerio V, Rapino M., Zaramella P., et al. (2014). Postnatal hyperoxia exposure differentially affects hepatocytes and liver haemopoietic cells in newborn rats. PubMed DOI PMC

Marshall J. C. (2014). Why have clinical trials in sepsis failed? PubMed DOI

Merx M. W., Liehn E. A., Janssens U., Lutticken R., Schrader J., Hanrath P., et al. (2004). HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. PubMed DOI

Morel J., Hargreaves I., Brealey D., Neergheen V., Backman J. T., Lindig S., et al. (2017). Simvastatin pre-treatment improves survival and mitochondrial function in a 3-day fluid-resuscitated rat model of sepsis. PubMed DOI

Nežić L., Škrbić R., Amidžić L., Gajanin R., Kuča K., Jaćević V. (2018). Simvastatin protects cardiomyocytes against endotoxin-induced apoptosis and up-regulates survivin/NF-κB/p65 expression. PubMed DOI PMC

Nežić L., Skrbić R., Dobrić S., Stojiljković M. P., Jaćević V., Satara S. S., et al. (2009a). Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. PubMed DOI

Nežić L., Skrbic R., Dobric S., Stojiljkovic M. P., Satara S. S., Milovanovic Z. A., et al. (2009b). Effect of simvastatin on proinflammatory cytokines production during lipopolysaccharide-induced inflammation in rats. PubMed

Oami T., Watanabe E., Hatano M., Teratake Y., Fujimura L., Sakamoto A., et al. (2018). Blocking liver autophagy accelerates apoptosis and mitochondrial injury in hepatocytes and reduces time to mortality in a murine sepsis model. PubMed DOI

Scheer A., Knauer S. K., Verhaegh R. (2017). Survivin expression pattern in the intestine of normoxic and ischemic rats. PubMed DOI PMC

Seemann S., Zohles F., Lupp A. (2017). A comprehensive comparison of three different animal models for systemic inflammation. PubMed DOI PMC

Shinozaki S., Inoue Y., Yang W., Fukaya M., Carter E. A., Yu Y. M., et al. (2010). Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice. PubMed DOI PMC

Singer M., Deutschman C. S., Seymour C. W., Shankar-Hari M., Annane D., Bauer M., et al. (2016). The third international consensus definitions for sepsis and septic shock (Sepsis-3). PubMed DOI PMC

Slotta J. E., Laschke M. W., Schilling M. K., Menger M. D., Jeppsson B., Thorlacius H. (2010). Simvastatin attenuate hepatic sensitization to lipopolysaccharide after partial hepatectomy. PubMed DOI

Smeding L., Plötz F. B., Groeneveld A. J., Kneyber M. C. (2012). Structural changes of the heart during severe sepsis or septic shock. PubMed DOI

Vincent J. L., Opal S. M., Marshall J. C., Tracey K. J. (2013). Sepsis definitions: time for a change. PubMed DOI PMC

Wang K. (2015). Molecular mechanisms of hepatic apoptosis regulated by nuclear factors. PubMed DOI

Wang K., Brems J. J., Gamelli R. L., Holterman A. X. (2010). Survivin signalling is regulated through the nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis. PubMed DOI

Wang Y., Yang W., Zhao X., Zhang R. (2018). Experimental study of the protective effect of simvastatin on lung injury in rats with sepsis. PubMed DOI

Wilson R. L., Selvaraju V., Lakshmanan R., Thirunavukkarasu M., Campbell J., McFadden D. W., et al. (2017). Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice. PubMed DOI PMC

Yan J., Li S., Li S. (2014). The role of the liver in sepsis. PubMed DOI PMC

Zeng W., Li H., Chen Y., Lv H., Liu L., Ran J., et al. (2016). Survivin activates NF-κB p65 via the IKKβ promoter in esophageal squamous cell carcinoma. PubMed DOI

Zhang S., Luo L., Wang Y., Rahman M., Lepsenyi M., Syk L., et al. (2012). Simvastatin protects against T cell immune dysfunction in abdominal sepsis. PubMed DOI

Zhao G., Yu Y. M., Kaneki M., Bonab A. A., Tompkins R. G., Fischman A. J. (2015). Simvastatin reduces burn injury-induced splenic apoptosis via down-regulation of the TNF-α/ NF-κB pathway. PubMed DOI PMC

Zhao G., Yu Y. M., Kaneki M., Tompkins R. G., Fischman A. J. (2013). Simvastatin protects hepatocytes from apoptosis by suppressing the TNF-α/caspase-3 signalling pathway in mice with burn injury. PubMed DOI PMC

Overexpression of MRP1/ABCC1, Survivin and BCRP/ABCC2 Predicts the Resistance of Diffuse Large B-Cell Lymphoma to R-CHOP Treatment

Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-kB/p65 Pathway

Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells' Survival and Hindering Cytochrome C-Mediated Apoptosis

Acute Toxic Injuries of Rat's Visceral Tissues Induced by Different Oximes