Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice

X Li, R Luo, R Chen, L Song, S Zhang… - American Journal …, 2014 - journals.physiology.org
X Li, R Luo, R Chen, L Song, S Zhang, W Hua, H Chen
American Journal of Physiology-Heart and Circulatory Physiology, 2014journals.physiology.org
Recent studies in septic models have shown that myocardial calpain activity and TNF-α
expression increase during sepsis and that inhibition of calpain activation downregulates
myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism
underlying this pathological process is unclear. Thus, in the present study, we aimed to
explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α
expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce …
Recent studies in septic models have shown that myocardial calpain activity and TNF-α expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IκBα/NF-κB signaling activity, and TNF-α expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-α expression were increased and IκBα protein was degraded. Furthermore, NF-κB was activated, as indicated by increased NF-κB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor Ш and PD-150606 prevented the LPS-induced degradation of myocardial IκBα, NF-κB activation, and TNF-α expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IκBα protein degradation, and NF-κB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-κB activation, TNF-α expression, and myocardial dysfunction in septic mice through IκBα protein cleavage.
American Physiological Society