| First Author | Li X | Year | 2014 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 306 |
| Issue | 6 | Pages | H833-43 |
| PubMed ID | 24441549 | Mgi Jnum | J:209496 |
| Mgi Id | MGI:5568005 | Doi | 10.1152/ajpheart.00893.2012 |
| Citation | Li X, et al. (2014) Cleavage of IkappaBalpha by calpain induces myocardial NF-kappaB activation, TNF-alpha expression, and cardiac dysfunction in septic mice. Am J Physiol Heart Circ Physiol 306(6):H833-43 |
| abstractText | Recent studies in septic models have shown that myocardial calpain activity and TNF-alpha expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-alpha expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IkappaBalpha/NF-kappaB signaling linked myocardial calpain activity and TNF-alpha expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IkappaBalpha/NF-kappaB signaling activity, and TNF-alpha expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-alpha expression were increased and IkappaBalpha protein was degraded. Furthermore, NF-kappaB was activated, as indicated by increased NF-kappaB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor capital SHA, Cyrillic and PD-150606 prevented the LPS-induced degradation of myocardial IkappaBalpha, NF-kappaB activation, and TNF-alpha 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, IkappaBalpha protein degradation, and NF-kappaB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-kappaB activation, TNF-alpha expression, and myocardial dysfunction in septic mice through IkappaBalpha protein cleavage. |
