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Published on: April 19, 2011
Inhibition of IκB phosphorylation prevents load-induced cardiac dysfunction in mice
Tetsu Tanaka1, Masahito Ogawa, Jun-ichi Suzuki
1Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan.
Insights
Inhibition of nuclear factor-kappa B (NF-κB) activation using IMD-1041 effectively prevents cardiac dysfunction and fibrosis in a mouse model of pressure overload. This intervention mitigates cardiac hypertrophy progression to heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pharmacology
Background:
- Pressure overload is a primary cause of cardiac hypertrophy, often leading to heart failure.
- Nuclear factor-kappa B (NF-κB) plays a crucial role in cardiac hypertrophy progression, but its precise role remains unclear.
- Understanding NF-κB pathophysiology is vital for developing therapeutic strategies against pressure overload-induced heart disease.
Purpose of the Study:
- To investigate the efficacy of inhibiting NF-κB activation in ameliorating pressure overload-induced cardiac dysfunction.
- To evaluate the therapeutic potential of IMD-1041, an inhibitor of IκB kinase-β, in a murine model of cardiac hypertrophy.
Main Methods:
- A murine thoracic aortic constriction (TAC) model was employed to induce pressure overload.
- Mice received daily oral administration of IMD-1041 (100 mg·kg(-1)·day(-1)) or vehicle for 42 days.
- Cardiac function, hypertrophy, fibrosis, NF-κB activation markers (p65 expression/translocation), and matrix metalloproteinase-2 (MMP-2) activity were assessed.
Main Results:
- TAC induced significant left ventricular wall thickening, cardiac dysfunction, and increased heart/lung weights.
- IMD-1041 treatment suppressed cardiac hypertrophy, fibrosis, and cardiomyocyte hypertrophy development.
- IMD-1041 inhibited TAC-induced p65 expression and nuclear translocation, and reduced MMP-2 activity.
- Late-stage IMD-1041 treatment (days 28-42) improved fractional shortening and reduced fibrosis without affecting hypertrophy.
Conclusions:
- Inhibition of NF-κB activation by IMD-1041 effectively prevents cardiac dysfunction and fibrosis in pressure overload-induced cardiac hypertrophy.
- IMD-1041 demonstrates potential in halting the transition from cardiac hypertrophy to heart failure.
- Targeting NF-κB activation represents a promising therapeutic strategy for managing pressure overload-induced cardiac pathologies.
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.
