ABSTRACT
AIMS: Insulin/insulin-like growth factor-1 (IGF-1) signaling plays an important role in many biological processes. The class IA isoform of phosphoinositide 3-kinase (PI3K) is an important downstream effector of the insulin/IGF-1 signaling pathway. The aim of this study is to examine the effect of persistent activation of PI3K on gene expression and markers of cellular senescence in murine hearts. MAIN METHODS: Transgenic mice expressing a constitutively active PI3K in a heart-specific manner were analyzed at the ages of 3 and 20 months. Effects of persistent activation of PI3K on gene expression were comprehensively analyzed using microarrays. KEY FINDINGS: Upon comprehensive gene expression profiling, the genes whose expression was increased included those for several heat shock chaperons. The amount and nuclear localization of a forkhead box O (FOXO) protein was increased. In addition, the gene expression of insulin receptor substrate-2 decreased, and that of phosphatase and tensin homolog deleted on chromosome ten (PTEN) increased, suggesting that the persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling. The expression of markers of cellular senescence, such as senescence-associated beta-galactosidase activity, cell cycle inhibitors, proinflammatory cytokines, and lipofuscin, did not differ between old wild-type and caPI3K mice. SIGNIFICANCE: The persistent activation of PI3K modified the expression of molecules of insulin/IGF-1 signaling pathway in a transgenic mouse line. Markers of cellular senescence were not changed in the aged mutant mice.
Subject(s)
Cellular Senescence/physiology , Gene Expression Regulation/physiology , Heart/physiology , Insulin-Like Growth Factor I/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/physiology , Age Factors , Analysis of Variance , Animals , Blotting, Western , Echocardiography , Enzyme Activation/physiology , Fluorescent Antibody Technique , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microarray Analysis , Real-Time Polymerase Chain Reaction , SirolimusABSTRACT
BACKGROUND: Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. METHODS AND RESULTS: We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. CONCLUSIONS: Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.
Subject(s)
Aging/metabolism , Myocardium/enzymology , Phosphoinositide-3 Kinase Inhibitors , Aging/pathology , Animals , Class I Phosphatidylinositol 3-Kinases , Mice , Mice, Transgenic , Myocardium/pathology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/physiologyABSTRACT
BACKGROUND: Diabetes mellitus is an independent risk factor for heart failure. Diabetes mellitus causes other age-related cardiovascular diseases. We assessed the hypothesis that hearts from diabetic animals are associated with accelerated aging processes. We also examined the effect of an angiotensin II receptor blocker (ARB) on the expression of senescence-associated molecules. METHODS AND RESULTS: We administered an ARB (candesartan 10 mg/kg per day) or saline to diabetic db/db or control db/+ mice. The treatment was started when mice were 10-weeks-old, and continued for 15 weeks. Systolic function was impaired in db/db mice and candesartan improved cardiac function. The amount of phosphorylated Akt and S6 was decreased in saline-treated db/db mice, and candesartan treatment partially preserved phosphorylation. The amount of p21, p27, p53 or Rb was increased in the heart tissue of saline treated db/db mice. Candesartan treatment completely suppressed the increases of p21, p27, p53 and Rb. CONCLUSIONS: An ARB improved cardiac function of diabetic animals, and this was accompanied by decreases of senescence-associated molecules in the myocardium. ARB may be a modality for heart failure patients with diabetes mellitus.
