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http://purl.uniprot.org/citations/19318376http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/19318376http://www.w3.org/2000/01/rdf-schema#comment"

Aims

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.

Methods and 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.

Conclusion

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."xsd:string
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http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Chen R."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Li Y."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Li X."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Peng T."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Shan L."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/author"Shen E."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/date"2009"xsd:gYear
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/name"Cardiovasc Res"xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/pages"72-79"xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/title"Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxaemia."xsd:string
http://purl.uniprot.org/citations/19318376http://purl.uniprot.org/core/volume"83"xsd:string
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