Journal Article

Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxaemia

Xiaoping Li, Ying Li, Limei Shan, E Shen, Ruizhen Chen and Tianqing Peng

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 83, issue 1, pages 72-79
Published in print July 2009 | ISSN: 0008-6363
Published online March 2009 | e-ISSN: 1755-3245 | DOI: https://dx.doi.org/10.1093/cvr/cvp100
Over-expression of calpastatin inhibits calpain activation and attenuates myocardial dysfunction during endotoxaemia

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Aims

Lipopolysaccharide (LPS) induces cardiomyocyte caspase-3 activation and proinflammatory factors, in particular tumour necrosis factor-alpha (TNF-α) 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-α expression, and myocardial dysfunction during LPS stimulation.

Methods and results

In cultured adult rat cardiomyocytes, LPS (1 µg/mL) induced calpain and caspase-3 activity, and up-regulated TNF-α 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 gp91phox-NADPH oxidase prevented calpain and caspase-3 activation and decreased TNF-α 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-α expression were also reduced in CAST-Tg and calpain inhibitor-III compared with wild-type and vehicle-treated hearts, respectively.

Conclusion

gp91phox-NADPH oxidase-mediated calpain-1 activation induces caspase-3 activation and TNF-α 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.

Keywords: Calpastatin; Calpain; Sepsis; TNF-alpha; Caspase-3; Heart; Myocardial dysfunction

Journal Article.  4997 words.  Illustrated.

Subjects: Cardiovascular Medicine

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