Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.

The signaling pathway of insulin/insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt is known to regulate longevity as well as resistance to oxidative stress in the nematode Caenorhabditis elegans. This regulatory process involves the activity of DAF-16, a forkhead transcription factor. Although reduction-of-function mutations in components of this pathway have been shown to extend the lifespan in organisms ranging from yeast to mice, activation of Akt has been reported to promote proliferation and survival of mammalian cells. Here we show that Akt activity increases along with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, and inhibition of forkhead transcription factor FOXO3a by Akt is essential for this growth arrest to occur. FOXO3a influences p53 activity by regulating the level of reactive oxygen species. These findings reveal a novel role of Akt in regulating the cellular lifespan and suggest that the mechanism of longevity is conserved in primary cultured human cells and that Akt-induced senescence may be involved in vascular pathophysiology.

Background-Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined. Methods and Results-Ang

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overloadinduced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.

Objective-Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD ϩ -dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood. Methods and Results-Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes. Key Words: cellular senescence Ⅲ p53 Ⅲ diabetes T he NAD ϩ -dependent histone deacetylase Sir2 induces longevity in yeast in response to calorie restriction signals. 1 SIRT1, a mammalian homologue of Sir2 and a member of the Sir2 family called sirtuins, has been shown to target p53, 2-4 Ku70, 5 and the forkhead transcription factors 6 -8 for deacetylation, thereby regulating stress responses, apoptosis, and cellular senescence. Acetylation of p53 is known to be crucial for its stabilization and transcriptional activation. 9 Accumulating evidence suggests that SIRT1 also modulates the metabolism of glucose and fat by interacting with peroxisome proliferator-activated receptor (PPAR) ␥ through nuclear receptor corepressor to repress adipogenesis, 10 modifying PPAR ␥ coactivator-1␣ to regulate hepatic glucose homeostasis 11,12 and regulating insulin secretion levels as well as insulin sensitivity. [13][14][15] Treatment with the sirtuin activator resveratrol has been shown to improve diet-induced obesity and insulin resistance 16,17 and delay age-related deterioration including increased arterial stiffness. 18 Moreover, Sirt1 has been reported to control endothelial angiogenic functions during postnatal vascular growth. 19 However, it remains unclear whether SIRT1 is involved in the pathogenesis of diabetes and its complications including diabetic vasculopathy. Conclusions-TheseVascular cells have a finite lifespan when cultured and eventually undergo senescence. Many of the changes seen in senescent vascular cells are consistent with those that occur in age-related vascular diseases. 20,21 Moreover, senescent vascular cells have been detected in human atherosclerotic tissues and exhibit various functional abnormalities, 22 suggesting that senescence of vascular cells contributes to the pathophysiology of age-related vascular diseases. There is also in vivo evidence for the occurrence of vascular cell senescence in diabetic vasculopathy. 23 Given that CR augments SIRT1 activity...