Abstract 17891: NF-κB Signaling Plays a Crucial and Detrimental Role in Cardiomyocyte Senescence
Introduction: Emerging evidence indicates that senescent cardiomyocytes are responsible for the development of cardiac dysfunction in aging heart. Evidence also indicates that NF-κB activity increases in aged cells. However, the role of NF-κB signaling in cardiomyocyte senescence remains virtually unknown.
Hypothesis: We hypothesized that cardiomyocyte-specific inhibition of NF-κB would protect against cardiomyocyte senescence.
Methods: Doxorubicin (Dox) was used to induce cellular senescence in adult mouse cardiomyocytes and H9c2 cells. Myocytes were isolated from transgenic (Tg) mice overexpressing a mutant IκBα protein that inhibits constitutive NF-κB activation specifically in cardiomyocytes, and their non-transgenic (NTg) littermates. PDTC was used to inhibit NF-κB in H9c2 cells. The extent of cellular senescence and the underlying signaling pathways were assessed in young and aged (10- and 86-wk-old) Tg and NTg mice by senescence associated-β gal (SA-β gal) staining and Western immunoblot.
Results: Dox activated cellular senescence signaling pathway p53/p21 with activation of NF-κB (p65) in H9c2 cells and NTg cells (Figure). These responses were blunted by treatment with PDTC, and also in Tg cardiomyocytes. This was associated with a significant decrease in cellular senescence, compared with Dox treatment only and NTg cardiomyocytes (Figure). Consistently, three senescent pathways (p53/p21, p16, and Akt/GSK-3β) were blunted in aged Tg mouse hearts with inhibition of constitutive NF-κB activation. The number of senescent cells was significantly less in aged Tg mice. Furthermore, p38/ERK of cytoprotective signaling was preserved in aged Tg hearts.
Conclusions: Taken together, these in vivo and in vitro observations identify a critical negative influence of NF-κB signaling on cardiomyocyte senescence. These findings may have significant therapeutic implications for the elderly patients with heart failure.
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. Y. Yang: None. J. Hauptman: None. R. Vincent: None. B. Dawn: None.
- © 2016 by American Heart Association, Inc.