Abstract 12143: A Constitutive Activation of Phosphoinositide 3-kinase Modifies Cardiac Aging in Mice
Background: Heart failure is a typical age-associated disease. Suppression of phosphoinositide 3-kinase (PI3K) is reported to prevent many of the age-related cardiac changes in mice. We tested the hypothesis that a constitutive activation of PI3K deteriorated age-related changes of heart.
Methods and Results: We analyzed young (3-months old) and old (18–20 months old) transgenic mice expressing a constitutive active PI3K (caPI3K) in heart or non-transgenic (NTg) mice. Survival was not different between caPI3K and NTg mice until 20 months of age. Upon cardiac catheterization under dobutamine infusion, max dP/dT of old caPI3K mice was lower than that of old NTg mice. Heart weight was increased by 1.2 fold in caPI3K mice at both ages. TBARS, a marker of oxidative stress, was increased by 1.5 fold in old caPI3K mice compared to that in old NTg mice. The extent of myocardial fibrosis was increased in old caPI3K mice compared to old NTg mice (3.0 ± 0.3% vs. 1.6 ± 0.2%, area in %, P<0.05). The expression of markers of cellular senescence, such as senescence-associated beta-galactosidase activity, cell cycle inhibitors, proinflammatory cytokines, lipofuscin was not different. A comprehensive microarray analysis (6 arrays used for individual hearts in each group) showed that increased expression of heat shock protein genes and detoxification genes in caPI3K mice. Among the genes involved in PI3K signal, PTEN expression was increased, and IRS2 and AKT2 expressions were decreased. IGF-1 induced phosphorylation of a FOXO protein was attenuated in caPI3K mice, suggesting that constitutive activation of PI3K might cause cellular insulin resistance.
Conclusions: The age-associated decrease in cardiac function deteriorated in a caPI3K transgenic line. However, cardiac aging appeared to be attenuated by compensatory mechanisms.
- © 2010 by American Heart Association, Inc.