Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice

Tanaka T, Ogawa M, Suzuki J, Sekinishi A, Itai A, Hirata Y, Nagai R, Isobe M. Inhibition of I kappa B phosphorylation prevents load-induced cardiac dysfunction in mice. Am J Physiol Heart Circ Physiol 303: H1435-H1445, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00290.2012.-Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-kappa B is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-kappa B activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-kappa B activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of I kappa B via inhibition of I kappa B kinase-beta. IMD-1041 (100 mg.kg(-1).day(-1)) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65-positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC-treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-kappa B activation.