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

Abstract

Recent studies in septic models have shown that myocardial calpain activity and TNF-␣ expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-␣ expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IB␣/NF-B signaling linked myocardial calpain activity and TNF-␣ expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IB␣/NF-B signaling activity, and TNF-␣ expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-␣ expression were increased and IB␣ protein was degraded. Furthermore, NF-B was activated, as indicated by increased NF-B p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor and PD-150606 prevented the LPS-induced degradation of myocardial IB␣, NF-B activation, and TNF-␣ 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, IB␣ protein degradation, and NF-B activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-B activation, TNF-␣ expression, and myocardial dysfunction in septic mice through IB␣ protein cleavage. sepsis; calpain; tumor necrosis factor-␣; IB␣/nuclear factor-B; myocardial dysfunction APPROXIMATELY 700,000 cases of sepsis occur each year in the United States, and this condition has an overall mortality rate of ϳ30% (1). Myocardial dysfunction is an early and fatal manifestation of sepsis in humans and animals (21,25,26), but the physiological basis of this effect and the molecular mediators that trigger myocardial dysfunction are not yet fully understood.Calpains are a family of Ca 2ϩ

Calpain-dependent regulation of the skeletal muscle atrophy following unloading

“…The PD150606 dose used in our experiments is comparable to previously published data on intraperitoneal injections in mice (21) but lower than previously published data on intraperitoneal injections in rats (22). Since in our experiments PD150606 was administered intramuscular around soleus muscle the overall muscle concentration was sufficient to achieve the calpain inhibitory effects comparable to previously published data (21), (22). The control animals received equal volumes of 1% DMSO/saline vehicle solution.…”

Crosstalk between calpain activation and TGF-β1 augments collagen-I synthesis in pulmonary fibrosis

“…In the current study, we revealed that calpain mediates TGF-β1 protein synthesis in the HLFs. Moreover, it has been reported that calpain mediates dendritic protein synthesis in hippocampal tissues and neurons [26], and induces higher expression of TNF-α mRNA and protein in myocardial tissues [27]. Tabata and colleagues reported that bleomycin induced increases of TGF-β1 mRNA, which was suppressed significantly by the administration of a calpain inhibitor [14].…”

“…Mice were treated with calpain inhibitor, calpeptin for the first 14 days (days 0-14) or the last 14 days (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] in the bleomycin-induced model. The administration of calpeptin for the first 14 days or the last 14 days prevented bleomycin-induced pulmonary fibrosis equally (35.4% decrease, 31.3% decrease).…”

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

“…Moreover, prolonged exposure of paclitaxel increases calpain activity in primary rat dorsal root ganglion (DRG) and human neuroblastoma cells (Boehmerle et al, 2007). Recent reports suggested that IkB/NF-kB signaling remains a potential link between myocardial calpain activation and TNF-a expression in mice, in which treatment with calpain inhibitor markedly decreases TNF-a mRNA expression and improves cardiac dysfunction (Li et al, 2009a(Li et al, , 2014. Calcium channels and ryanodine receptors induce reactive oxygen species (ROS)-mediated calpain activation in high glucose-stimulated cardiomyocytes and hyperglycemic hearts.…”