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OBJECTIVE
Lipopolysaccharide (LPS) induces cardiomyocyte caspase-3 activation and proinflammatory factors, in particular tumour necrosis factor-alpha (TNF-alpha) production, both of which contribute to myocardial dysfunction during sepsis. The present study was to investigate the roles of calpain/calpastatin system in cardiomyocyte caspase-3 activation, TNF-alpha expression, and myocardial dysfunction during LPS stimulation.RESULTS
In cultured adult rat cardiomyocytes, LPS (1 microg/mL) induced calpain and caspase-3 activity, and up-regulated TNF-alpha expression. These effects of LPS were abrogated by over-expression of calpastatin, an endogenous calpain inhibitor, transfection of calpain-1 siRNA, or various pharmacological calpain inhibitors. Furthermore, blocking gp91(phox)-NADPH oxidase prevented calpain and caspase-3 activation and decreased TNF-alpha expression in LPS-stimulated cardiomyocytes. To investigate the role of calpastatin in endotoxaemia, transgenic mice with calpastatin over-expression (CAST-Tg) and wild-type mice were treated with LPS (4 mg/kg, i.p.) or saline in the presence of calpain inhibitor-III (10 mg/kg, i.p.) for 4 h, and their heart function was measured with a Langendorff system. Over-expression of calpastatin significantly attenuated myocardial dysfunction (P < 0.05). Consistently, calpain activity, caspase-3 activity, and TNF-alpha expression were also reduced in CAST-Tg and calpain inhibitor-III compared with wild-type and vehicle-treated hearts, respectively.CONCLUSIONS
gp91(phox)-NADPH oxidase-mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation. Over-expression of calpastatin inhibits calpain activation and improves myocardial function in endotoxaemia. The present study suggests that targeting calpain/calpastatin system may be a potential therapeutic intervention for septic hearts.
caspase-3 → Lipopolysaccharide (LPS): " Lipopolysaccharide (LPS) induces cardiomyocyte caspase-3 activation and proinflammatory factors, in particular tumour necrosis factor-alpha (TNF-alpha) production, both of which contribute to myocardial dysfunction during sepsis "
calpain → LPS: " In cultured adult rat cardiomyocytes, LPS ( 1 microg/mL ) induced calpain and caspase-3 activity, and up-regulated TNF-alpha expression "
TNF-alpha → LPS: " In cultured adult rat cardiomyocytes, LPS ( 1 microg/mL ) induced calpain and caspase-3 activity, and up-regulated TNF-alpha expression "
caspase-3 → LPS: " In cultured adult rat cardiomyocytes, LPS ( 1 microg/mL ) induced calpain and caspase-3 activity, and up-regulated TNF-alpha expression "
LPS → calpain inhibitor-III: " To investigate the role of calpastatin in endotoxaemia, transgenic mice with calpastatin over-expression ( CAST-Tg ) and wild-type mice were treated with LPS ( 4 mg/kg, i.p. ) or saline in the presence of calpain inhibitor-III ( 10 mg/kg, i.p. ) for 4 h, and their heart function was measured with a Langendorff system "
calpain-1 → gp91(phox)-NADPH oxidase: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
calpain-1 → gp91(phox)-NADPH: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
TNF-alpha → calpain-1: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
TNF-alpha → gp91(phox)-NADPH oxidase: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
TNF-alpha → gp91(phox)-NADPH: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
caspase-3 → calpain-1: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
caspase-3 → gp91(phox)-NADPH oxidase: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
caspase-3 → gp91(phox)-NADPH: " gp91(phox)-NADPH oxidase mediated calpain-1 activation induces caspase-3 activation and TNF-alpha expression in cardiomyocytes during LPS stimulation "
calpain ⊣ calpastatin: " Over-expression of calpastatin inhibits calpain activation and improves myocardial function in endotoxaemia "