Simvastatin Protects Cardiomyocytes Against Endotoxin-induced Apoptosis and Up-regulates Survivin/NF-κB/p65 Expression
Language English Country England, Great Britain Media electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30279549
PubMed Central
PMC6168467
DOI
10.1038/s41598-018-32376-4
PII: 10.1038/s41598-018-32376-4
Knihovny.cz E-resources
- MeSH
- Administration, Oral MeSH
- Apoptosis drug effects MeSH
- Escherichia coli MeSH
- Myocytes, Cardiac drug effects pathology MeSH
- Cardiomyopathies etiology pathology prevention & control MeSH
- Caspase 3 metabolism MeSH
- Rats MeSH
- Humans MeSH
- Lipopolysaccharides toxicity MeSH
- Disease Models, Animal MeSH
- Myocardium cytology pathology MeSH
- Rats, Wistar MeSH
- Sepsis complications etiology MeSH
- Signal Transduction drug effects MeSH
- Simvastatin administration & dosage MeSH
- Heart drug effects MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage MeSH
- Survivin metabolism MeSH
- Transcription Factor RelA metabolism MeSH
- Up-Regulation drug effects MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Birc5 protein, rat MeSH Browser
- Casp3 protein, rat MeSH Browser
- Caspase 3 MeSH
- Lipopolysaccharides MeSH
- Rela protein, rat MeSH Browser
- Simvastatin MeSH
- Hydroxymethylglutaryl-CoA Reductase Inhibitors MeSH
- Survivin MeSH
- Transcription Factor RelA MeSH
This study is aimed to investigate whether simvastatin induces cardiomyocytes survival signaling in endotoxin (lipopolysaccharide, LSP)-induced myocardial injury, and if so, further to determine a role of survivin in simvastatin-anti-apoptotic effect. Wistar rats were pretreated with simvastatin (10-40 mg/kg po) before a single non-lethal dose of LPS. In myocardial tissue, LPS induced structural disorganization of myofibrils with significant inflammatory infiltrate (cardiac damage score, CDS = 3.87 ± 0.51, p < 0.05), whereas simvastatin dose-dependently abolished structural changes induced by LPS (p < 0.01). Simvastatin in 20 mg/kg and 40 mg/kg pretreatment, dose dependently, attenuated myocardial apoptosis determined as apoptotic index (28.8 ± 4.5% and 18.9 ± 3.5, p < 0.05), decreased cleaved caspase-3 expression (32.1 ± 5.8%, p < 0.01), along with significant Bcl-xL expression in the simvastatin groups (p < 0.01). Interestingly, in the simvastatin groups were determined significantly increased expression of survivin (p < 0.01), but in negative correlation with cleaved caspase-3 and apoptotic indices (p < 0.01). Simvastatin has a cardioprotective effects against LPS induced apoptosis. The effect may be mediated by up-regulation of survivin via activation of NF-κB, which leads to reduced activation of caspase-3 and consequent apoptosis of cardiomyocytes in experimental sepsis.
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Li Y, Ge S, Peng Y. Inflammation and cardiac dysfunction during sepsis, muscular dystrophy, and myocarditis. Burns Trauma. 2013;1:109–121. doi: 10.4103/2321-3868.123072. PubMed DOI PMC
Romero-Bermejo FJ, et al. Sepsis-induced cardiomyopathy. Curr. Cardiol. Rev. 2011;7:163–183. doi: 10.2174/157340311798220494. PubMed DOI PMC
Hobai IA, et al. Dysregulation of intracellular calcium transporters in animal models of sepsis induced cardiomyopathy. Shock. 2015;43:3–15. doi: 10.1097/SHK.0000000000000261. PubMed DOI PMC
Cimolai MC, et al. Mitochondrial Mechanisms in Septic Cardiomyopathy. Int. J. Mol. Sci. 2015;16:17763–17778. doi: 10.3390/ijms160817763. PubMed DOI PMC
Smeding L, et al. Structural changes of the heart during severe sepsis or septic shock. Shock. 2012;37:449–456. doi: 10.1097/SHK.0b013e31824c3238. PubMed DOI
Lancel S, et al. Ventricular myocyte caspases are directly responsable for endotoxin-induced cardiac dysfunction. Circulation. 2005;111:2596–2604. doi: 10.1161/CIRCULATIONAHA.104.490979. PubMed DOI
Buerke U, et al. Apoptosis contributes to septic cardiomyopathy and is improved by simvastatin therapy. Shock. 2008;29:497–503. doi: 10.1097/SHK.0b013e318142c434. PubMed DOI
Fauvel H, Marchetti P, Chopin C, Formstecher P, Neviere R. Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. Am. J. Physiol. Heart. Circ. Physiol. 2001;280:H1608–H1614. doi: 10.1152/ajpheart.2001.280.4.H1608. PubMed DOI
Nežić L, et al. Effect of simvastatin on proinflammatory cytokines production during lipopolysaccharide-induced inflammation in rats. Gen. Physiol. Biophys. 2009;28:119–126. PubMed
Nežić L, et al. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Basic Clin. Pharmacol. Toxicol. 2009;104:185–191. doi: 10.1111/j.1742-7843.2008.00302.x. PubMed DOI
Slotta JE, et al. Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase reduces leukocyte recruitment and hepatocyte apoptosis in endotoxin-induced liver injury. J. Investig. Med. 2009;57:645–649. doi: 10.2310/JIM.0b013e3181a23cb0. PubMed DOI
Wang Y, et al. An experimental study of the protective effect of simvastatin on sepsis-induced myocardial depression in rats. Biomed. Pharmac. Ther. 2017;94:705–711. doi: 10.1016/j.biopha.2017.07.105. PubMed DOI
Tsang TJ, et al. Subcellular Localization of Survivin Determines Its Function in Cardiomyocytes. Theranostics. 2017;7:4577–4590. doi: 10.7150/thno.20005. PubMed DOI PMC
Dutta J, et al. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene. 2006;25:6800–6816. doi: 10.1038/sj.onc.1209938. PubMed DOI
Bo L, et al. Research on the function and mechanism of survivin in heart failure mice model. Eur. Rev. Med. Pharmacol. Sci. 2017;21:3699–3704. PubMed
Si R, et al. Survivin: a novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury. J. Mol. Cell. Cardiol. 2011;50:16–24. doi: 10.1016/j.yjmcc.2010.08.017. PubMed DOI
Lee BS, et al. Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin. PLoS ONE. 2015;10(8):e0135438. doi: 10.1371/journal.pone.0135438. PubMed DOI PMC
Chen CH, et al. Fluvastatin ameliorates endotoxin induced multiple organ failure in conscious rats. Resuscitation. 2007;74:166–174. doi: 10.1016/j.resuscitation.2006.12.002. PubMed DOI
La Mura V. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology. 2013;57:1172–1181. doi: 10.1002/hep.26127. PubMed DOI
Liu X, et al. Effects of HMG-CoA reductase inhibitor on experimental autoimmune myocarditis. Cardiovasc. Drugs Ther. 2012;26:121–130. doi: 10.1007/s10557-012-6372-6. PubMed DOI
Chopra M, Sharma AC. Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart. Pharmacol. Res. 2009;60:303–313. doi: 10.1016/j.phrs.2009.04.009. PubMed DOI PMC
Fu H, Wang QS, Luo Q. Simvastatin inhibits apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. World J. Emerg. Med. 2014;5:291–297. doi: 10.5847/wjem.j.issn.1920-8642.2014.04.009. PubMed DOI PMC
Levkau B. Survivin signaling in the heart. J. Mol. Cell. Cardiol. 2011;50:6–8. doi: 10.1016/j.yjmcc.2010.10.013. PubMed DOI
Wilson RL, et al. Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice. J. Surg. Res. 2017;220:68–78. doi: 10.1016/j.jss.2017.06.062. PubMed DOI PMC
Wang K, et al. Survivin signaling is regulated through nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis. Biochim. Biophys. Acta. 2010;12:1368–1375. doi: 10.1016/j.bbamcr.2010.08.008. PubMed DOI
Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat. Rev. Cancer. 2010;10:561–574. doi: 10.1038/nrc2889. PubMed DOI
Wang Y, et al. Experimental Study of the Protective Effect of Simvastatin on Lung Injury in Rats with Sepsis. Inflammation. 2018;41:104–113. doi: 10.1007/s10753-017-0668-4. PubMed DOI
Shinozaki S, et al. Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice. Biochem. Biophys. Res. Commun. 2010;391:1459–1464. doi: 10.1016/j.bbrc.2009.12.094. PubMed DOI PMC
Seemann S, Zohles F, Lupp A. Comprehensive comparison of three different animal models for systemic inflammation. J. Biomed. Sci. 2017;24:10–17. doi: 10.1186/s12929-017-0370-8. PubMed DOI PMC
Jaćević V, et al. Effects of fullerenol nanoparticles and amifostine on radiation-induced tissue damages: Histopathological analysis. J. Appl. Biomed. 2016;14:285–297. doi: 10.1016/j.jab.2016.05.004. DOI
Wu X, et al. N-acetylcysteine reduces oxidative stress, nuclear factor-κB activity and cardiomyocyte apoptosis in heart failure. Mol. Med. Rep. 2014;10:615–624. doi: 10.3892/mmr.2014.2292. PubMed DOI PMC
Zhang S, et al. Role of the JAK/STAT signaling pathway in the pathogenesis of acute myocardial infarction in rats and its effect on NF-κB expression. Mol. Med. Rep. 2013;7:93–98. doi: 10.3892/mmr.2012.1159. PubMed DOI
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