Abstract 14642: Cardiac-specific Transgenic Inhibition of NF-kB Attenuates Apoptosis and Remodeling in the Aging Heart

Abstract

Introduction: Aging increases the risk of cardiovascular diseases. Remodeling of the aged heart involves slow yet progressive loss of functional cardiomyocytes, reactive hypertrophy of the remaining cardiomyocytes, and increased fibrosis. NF-κB is one of the major transcription factors that have been linked to cardiovascular disease. Although NF-kB activity increases with aging and aging-related chronic diseases, its role in cardiomyocyte apoptosis and remodeling of the aging heart remains unclear. Hypothesis: We hypothesized that myocardial NF-kB signaling would aggravate ventricular remodeling in the aging heart. Methods: We used transgenic mice overexpressing a mutant IkBα that prevents NF-kB activation. Cardiac structure and function were assessed by echocardiography and morphometry in young (10-week-old) and aged (86-week-old) IkBα transgenic (Tg) mice and non-transgenic (NTg) littermates. Cardiomyocyte apoptosis and molecular regulators of apoptosis were quantified to gain molecular insights. Results: Compared with young NTg mice, aged NTg mice exhibited greater LV mass and LV end-diastolic volume (Fig). This age-related remodeling was significantly blunted in Tg hearts in the absence of myocardial NF-κB activation. The percentage of apoptotic cardiomyocyte nuclei in aged NTg myocardium was significantly higher compared with young NTg and young Tg hearts. Apoptosis was significantly attenuated in aged Tg hearts compared with aged NTg hearts. This decrease in cardiomyocyte apoptosis was corroborated by reduced Bax/Bcl-2 ratio in aged Tg hearts (Fig). Conclusions: We conclude that myocardial NF-kB signaling plays a detrimental role during cardiac aging process, and cardiac-specific NF-kB inhibition protects against cardiomyocyte apoptosis and age-associated LV remodeling. These molecular insights may be utilized to develop novel therapeutic strategies for cardiovascular diseases in the aging population.