Abstract
BackgroundRecent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates myocardial caspase-3 activation and apoptosis. However, the mechanism underlying this pathological process is unclear. Therefore, in this study, our aim was to explore whether the Hsp90/Akt signaling pathway plays a role in the induction of myocardial calpain activity, caspase-3 activation and apoptosis in the septic mice.MethodsAdult male C57 mice were injected with lipopolysaccharide (LPS, 4 mg/kg, i.p.) to induce sepsis. Next, myocardial caspase-3 activity and the levels of Hsp90/p-Akt (phospho-Akt) proteins were detected, and apoptotic cells were assessed by performing the TUNEL assay.ResultsIn the septic mice, there was an increase in myocardial calpain and caspase-3 activity in addition to an increase in the number of apoptotic cells; however, there was a time-dependent decrease in myocardial Hsp90/p-Akt protein levels. The administration of calpain inhibitors (calpain inhibitor-Ш or PD150606) prevented the LPS-induced degradation of myocardial Hsp90/p-Akt protein and its expression in cardiomyocytes in addition to inhibiting myocardial caspase-3 activation and apoptosis. The inhibition of Hsp90 by pretreatment with 17-AAG induced p-Akt degradation, and the inhibition of Akt activity by pretreatment with wortmannin resulted in caspase-3 activation in wildtype C57 murine heart tissues.ConclusionsMyocardial calpain induces myocardial caspase-3 activation and apoptosis in septic mice via the activation of the Hsp90/Akt pathway.
Highlights
Recent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates myocardial caspase-3 activation and apoptosis
The molecular and cellular mechanisms that mediate the pathogenesis of septic cardiomyopathy are still unclear, several lines of evidence suggest that myocardial caspase-3 activation plays a major role in myocardial dysfunction [3,4,5,6]
Both calpain inhibitor-III and PD150606 significantly inhibited the increase in myocardial calpain activity and caspase-3 activation (Figure 1C) in septic mice
Summary
Recent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates myocardial caspase-3 activation and apoptosis. In a recent study that we published, an increase in myocardial calpain activity in the septic mouse was noted [7,8], and in addition, over-expression of calpastatin, a specific inhibitor of calpain, or treatment with pharmacological inhibitors of calpain prevented myocardial caspase-3 activation during endotoxemia. These results suggest that calpain is involved in the activation of caspase-3 during sepsis [7]. The mechanisms involved in calpaininduced caspase-3 activation have not been completely defined in septic cardiomyocytes
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