Document Detail


Inhibition of I kappaB Phosphorylation Prevents Load-induced Cardiac Dysfunction in Mice.
MedLine Citation:
PMID:  23042949     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background: Pressure-overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor-kappaB (NF-kappaB) is a key factor in the progression of cardiac hypertrophy, its pathophisiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-kappaB activation improves pressure overload-induced cardiac dysfunction. Material and methods: To assess the effect of inhibition on NF-kappaB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IkappaB via inhibition of IKK-beta. IMD-1041 (100mg/kg/day) or vehicle was administered orally into the mice once a day, and the mice were sacrificed on day 42 after TAC. Results: TAC resulted in LV wall thickening, cardiac dysfunction and the increase of heart and lung weight, while IMD-1041 significantly suppressed its development 6 weeks after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle group, while IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65 positive cells, and the nuclear translocation of p65 induced by TAC compared to the vehicle group. MMP-2 activity increased in the vehicle+TAC group, however, it was suppressed in the IMD-1041+TAC group. The IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease of %FS and cardiac fibrosis without anti-hypertrophic effect. 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-kappaB activation.
Authors:
Tetsu Tanaka; Masahito Ogawa; Jun-Ichi Suzuki; Asuka Sekinishi; Akiko Itai; Yasunobu Hirata; Ryozo Nagai; Mitsuaki Isobe
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-5
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  -     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1.
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