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.

Background-The functional changes associated with cellular senescence may be involved in human aging and age-related vascular disorders. We have shown the important role of telomere and telomerase in vascular cell senescence in vitro. Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis, implying contributions to atherogenesis. However, whether senescent vascular cells are present in the vasculature and contribute to the pathogenesis of atherosclerosis remains unclear. Methods and Results-Senescence-associated ␤-galactosidase (␤-gal) activity was examined in the coronary arteries and the internal mammary arteries retrieved from autopsied individuals who had had ischemic heart diseases. Strong ␤-gal stainings were observed in atherosclerotic lesions of the coronary arteries but not in the internal mammary arteries. Key Words: aging Ⅲ atherosclerosis Ⅲ endothelium C ellular senescence is a limited ability of primary human cells to divide when cultured in vitro. This cessation of cell division is accompanied by a specific set of changes in cell function, morphology, and gene expression. These changes in cell phenotype may contribute to age-associated diseases, including atherosclerosis. However, cellular senescence has largely been investigated in vitro, and the presence of senescent vascular cells in vivo has not been clarified.Recently, accumulating evidence has suggested a critical role of telomere and telomerase in cellular senescence in vitro. 1 We have demonstrated previously that the introduction of telomerase catalytic component (TERT) into human vascular smooth muscle cells extends cell life span and preserves a younger phenotype, suggesting that telomere stabilization is important for long-term cell viability of vascular cells. 2 Progressive telomere shortening in human arteries has been observed in the regions susceptible to atherosclerosis. 3 Moreover, telomere length has been reported to inversely correlate with pulse pressure and atherosclerotic grade in human. 4,5 Although these observations imply that telomere shortening in vivo may contribute to the pathogenesis of age-associated vascular disorders, it remains unclear whether loss of telomere function induces vascular dysfunction associated with aging.In the present study, we demonstrate the presence of vascular endothelial cells with senescence-associated phenotypes in the atherosclerotic regions of human coronary arteries. We also show that loss of telomere function induces endothelial dysfunctions that are observed in aged arteries, whereas inhibition of telomere shortening suppresses these alterations with senescence. Methods Tissue SpecimensHuman coronary arteries and internal mammary arteries were obtained from 4 autopsied individuals who had ischemic heart diseases. The autopsy tissues were obtained within 12 hours after death and were subjected to ␤-galactosidase (␤-gal) staining. HistologySenescence-associated ␤-gal activity was examined in the tissues as described previously. 6 Briefly, t...

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