Simvastatin Protects Cardiomyocytes Against Endotoxin-induced Apoptosis and Up-regulates Survivin/NF-κB/p65 Expression

Abstract

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.

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

“…Here, we showed that one of the potential protective mechanisms of simvastatin against AKI is blockade of renal tubular cell apoptosis, confirmed by reduced cytochrome C and cleaved caspase-3 expression and corresponding DNA fragmentation. Interestingly, results of antiapoptotic actions of simvastatin through inhibition of pro-apoptotic Bim/Bax and effectors caspases have been well documented in hepatocytes and lymphocytes, and cardiomyocyte in other’s and our previous studies [ 20 , 21 , 28 , 29 ].…”

“…Further, simvastatin induced intense and dose-dependent expression of survivin in the tubular epithelium that is inversely correlated with cytochrome C and cleaved caspase-3 respectively, and indicates its evident anti-apoptotic effects. Because our previous studies indicated an important role of survivin/NF-κB/p65 pathway activation in cytoprotection against LPS-injury [ 20 , 21 ], similar to Wilson et al [ 37 ], in CLP-induced cardiomyopathy, we hypothesized that simvastatin has significant cell-protective effects in septic AKI but not only by inhibiting of apoptotic cell death but through induction of the important intracellular survival pathways in renal tubular epithelium.…”

“…Growing experimental evidence has shown that pretreatment with statins prevents tissue injuries induced by bacterial toxins [ 20 , 21 , 22 , 23 , 24 ]. Consistently, our work and the studies by Apaya et al [ 25 ] and Ozkok et al [ 26 ] demonstrated that simvastatin attenuated LPS-induced renal injury, seen as a significantly reduced amount of infiltrating leukocytes associated with minimal histopathological features.…”

“…In the context of the experimental sepsis, we have previously shown that simvastatin improved survival rate and significantly suppressed LPS-induced over-production of proinflammatory cytokines, TNFα and interleukin (IL)-1β [ 19 ]. Furthermore, the cell-protective effect of simvastatin pretreatment against LPS has been confirmed on cardiomyocytes [ 20 ], hepatocytes, and spleen lymphocytes [ 21 ]. These results showed that pretreatment with simvastatin mitigated myocardial, liver, and spleen tissue injuries, and decreased activation of the cleaved caspase-3 along to the reduced apoptotic-cell death in the parenchyma.…”

“…These results showed that pretreatment with simvastatin mitigated myocardial, liver, and spleen tissue injuries, and decreased activation of the cleaved caspase-3 along to the reduced apoptotic-cell death in the parenchyma. Simvastatin targets the cell-survival signaling pathway survivin/NF-κB/p65 and anti-apoptotic Bcl-XL in these cells, which appears a protective mechanism in response to LPS-induced tissue injury and programmed cell death [ 20 , 21 ].…”