title: Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice.
abstract: Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-κB 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-κB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-κB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IκB via inhibition of IκB kinase-β. 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-κB activation.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Asuka
authors.initials: A
authors.lastname: Sekinishi
authors.forename: Akiko
authors.initials: A
authors.lastname: Itai
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis / Q000517:prevention & control; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C579565:IMD-1041; D016328:NF-kappa B; D051550:I-kappa B Kinase; D020778:Matrix Metalloproteinase 2