Abstract 18099: Cardiac-Specific NF-κB Inhibition Protects Against Cardiomyocyte Senescence and Age-Related Cardiac Dysfunction
Introduction: Increasing evidence indicates that progressive cardiomyocyte aging contributes to the development of cardiac dysfunction in the elderly. The role of NF-κB, a central component of cellular response to damage, stress, and inflammation, in cardiac senescence remains unclear.
Hypothesis: We hypothesized that NF-κB signaling adversely impacts cardiomyocyte senescence.
Methods: Young and aged (10- and 86-wk-old) transgenic (Tg) mice overexpressing a physphorylation-resistant mutant IκBα molecule that specifically inhibits cardiac NF-κB activation, and their non-transgenic (NTg) littermates were used. Activation of NF-κB, cellular hypertrophy, myocardial fibrosis, oxidative stress, signaling pathways of cellular senescence, and cardiac structure and function were assessed comprehensively.
Results: Compared with young NTg hearts, aged NTg hearts showed greater activation of NF-κB along with molecular evidence of increased cellular senescence. These senescence associate changes were attenuated in aged Tg myocardium (Figure). Cardiomyocyte hypertrophy, myocardial fibrosis, and oxidative stress increased in aged NTg hearts, and were less evident in aged Tg mice. The activation of senescence-associated signaling pathways p53/p21 and p16 were blunted in aged Tg hearts (Figure). Consistent with these molecular changes, aged NTg hearts exhibited modest yet significant decrement in LVEF, which was prevented in Tg hearts. Together, these finding indicate that constitutive inhibition of NF-κB protects against myocyte aging.
Conclusions: We conclude that myocardial NF-κB signaling is detrimental for cardiomyocyte senescence. NF-kB inhibition may prove useful toward preventing age-related LV dysfunction in elderly patients.
Author Disclosures: S. Ye: None. G. Cheng: None. J. Lin: None. X. Chen: None. L. Zhao: None. A. Samanta: None. M. Girgis: None. A. Davani: None. A. Browning: None. Y. Yang: None. J. Hauptman: None. R. Vincent: None. B. Dawn: None.
- © 2016 by American Heart Association, Inc.