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.
Highlights
We and others have previously demonstrated that statins exert cholesterol-independent anti-inflammatory properties in models of acute local or systemic inflammation[9,10], such as protection of organ tissue injuries, apoptosis of macrophages and hepatocytes, respectively[11]
The major findings of the current study demonstrated that pretreatment with simvastatin dose-dependently prevented myocardial inflammatory injury, restrained apoptotic death of myocardial muscle cells and up-regulated expression of anti-apoptotic Bcl-xL and survivin
NF-kB expression was significantly increased following simvastatin pretreatment, indicating a possible downstream signaling mechanism by which simvastatin regulates survivin’s expression in experimental sepsis. These results demonstrate that survivin is a novel player in simvastatin-induced cardioprotection in experimental sepsis
Summary
We and others have previously demonstrated that statins exert cholesterol-independent anti-inflammatory properties in models of acute local or systemic inflammation[9,10], such as protection of organ tissue injuries, apoptosis of macrophages and hepatocytes, respectively[11]. Other authors showed that pretreatment with simvastatin protects against α-toxin induced sepsis that is associated with reduced proapoptotic mediators TNF-α and p53 expression, and cardiomyocyte apoptosis[7]. This simvastatin-triggered cardiomyocytes survival signaling and the mechanism of its anti-apoptotic effects remain unclear. The current study was design to determine whether pretreatment with simvastatin (1) prevents myocardial inflammatory injury and restrains apoptotic death of myocardial muscle cells, if yes (2) up-regulates survivin expression and (3) to identify the possible downstream signaling mechanism by which simvastatin regulates survivin’s expression in experimental sepsis
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