Abstract 19541: Age-Related Cardiac Dysfunction is Associated With Enhanced Oxidative Stress in Cardiac Senescence-Prone Mice
Advanced age is a significant risk factor for cardiovascular disease. Age-related cardiac remodeling is characterized by cardiomyocyte loss, hypertrophy, and fibrosis leading to diastolic and systolic dysfunction. We used the senescence-accelerated mouse (SAM) model to investigate age-related cardiac dysfunction and the role of oxidative stress. Echocardiography performed on 11 month old senescence-prone (SAMP) and senescence-resistant mice (SAMR) showed fractional shortening was significantly reduced (37.3% ± 3 vs. 29.9% ± 3; n=8, p<0.02). The end-diastolic diameter and end-systolic diameter significantly increased in the SAMP mice (EDD, 0.36 vs. 0.41 cm, p<0.05; ESD, 0.23 vs. 0.29 cm, p<0.01) consistent with cardiac remodeling. SAMP cardiomyocytes paced at increasing frequencies had a significant decrease in fractional shortening (n=5, p<0.001) and prolonged re-lengthening (n=5, p<0.05) compared to SAMR controls. Ca2+ transients were evaluated and a significant difference in resting Ca2+, Ca2+ extrusion, and the rate of Ca2+ release (n=5, p<0.05) were noted in the SAMP cardiomyocytes. SAMP myocytes had a 5–6 fold increase in expression of fetal phenotype markers β-MHC and ANF (n=5, p<0.05). Likewise, expression of senescence markers p16 and p19 were increase 50% and 300% (n=7, p<0.05). Histological sections from SAMP hearts showed a 2-fold increase in 8-oxoguanine staining consistent with enhanced oxidized DNA and cumulative oxidative stress (n=4, p<0.01). This correlated with a 2–3 fold enhanced expression of NADPH oxidases (Nox) 2 and 4 (n=5, p<0.05), but antioxidant enzymes superoxide dismutase, catalase, and peroxiredoxin III were unchanged. Foxo3A, an oxidant-sensitive transcription factor was upregulated 30-fold in 11 month old SAMP cardiomyocytes (n=5, p<0.01). Similarly, atrogin-1, a downstream effector of Foxo3A and component of the ubiquitin-ligase complex was increased 9-fold in SAMP cardiomyocytes (n=5, p<0.05). In conclusion age-related cardiac remodeling and dysfunction is associated with an increase in oxidative stress and up-regulation of Nox2 and Nox4 without an increase in antioxidant enzymes. Additionally, Nox2 and Nox4 may be modulating oxidant stress through a Foxo3A/atrogin-1 pathway.
- © 2010 by American Heart Association, Inc.