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.
Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).
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
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...
Abstract-Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity. (Circ Res. 2006;98:532-539.)Key Words: senescence Ⅲ clock gene Ⅲ aging Ⅲ CREB Ⅲ ERK C ellular senescence is a limited ability of primary human cells to divide when cultured in vitro and is accompanied by a specific set of phenotypic changes in morphology and gene expression and function. These phenotypic changes have been suggested to play a role in human aging and age-associated diseases. 1 This hypothesis of cellular aging was established by Hayflick 2 and is supported by the evidence that the replicative potential of primary cultured human cells is dependent on donor age and that the growth potential of cultured cells is correlated well with the mean maximum lifespan of the species of origin. 2 We have previously reported that senescent vascular cells are predominately localized in the plaque of human atherosclerosis but not in normal lesions and that vascular cell senescence results in vascular dysfunction. 3 Recently, we also demonstrated that atherogenic stimulation induces vascular cell senescence and vascular inflammation, thereby contributing to the development of atheroma. 4 There is also evidence indicating that progressive telomere shortening, a biomarker of cellular aging, occurs in human blood vessels, which may be related to age-associated vascular diseases. 5-10 Thus, vascular cell senescence in vivo may contribute to the pathogenesis of vascular aging. 11Aging is associated with a variety of alterations of circadian rhythms. 12,13 These include impairment of the rhythms for blood pressure, locomoto...
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