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Kaoru Tateno

Publications and source records attributed to Kaoru Tateno.

12 recordsLinked to original sources
PubMed2006

Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway.

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 II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II. CONCLUSIONS: We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.

Aging, Premature↗
PubMed2006

Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization.

The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1beta (IL-1beta). We then examined an experimental model of limb ischemia using IL-1beta-deficient mice. Implantation of IL-1beta-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1beta-deficient mononuclear cells increased expression of IL-1beta and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1beta markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.

Aged↗
PubMed2006

Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.

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.

Animals↗
PubMed2006

Application of hematopoietic cells to therapeutic angiogenesis.

Despite considerable progress in the field of cardiovascular medicine and surgery, ischemic heart disease is still the leading cause of death in advanced countries. In this context, it is no wonder why therapeutic angiogenesis, a way to ameliorate ischemic tissue from suffering dysfunction by increasing new blood vessels, gains so much attention from both clinicians and patients. In this review, we will briefly go through a decade of history in therapeutic angiogenesis including unraveling of its mechanisms, results obtained from clinical trials, and lessons learned from earlier investigations. We will then focus on an emerging, yet rapidly evolving field of hematopoietic cell therapy. Recent excellent studies seem to have brought us to the place where we might save so many patients from burden of ischemia, we should be aware that there are some controversies, and sometimes misunderstandings, regarding how or why this treatment does actually work, and what better way should we explore in order to get the best of its efficacy. With these caveats in mind, we will investigate the works elucidating the mechanisms and clinical efficacies of hematopoietic cell therapy.

Animals↗
PubMed2004

Akt-induced cellular senescence: implication for human disease.

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases 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, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.

Animals↗
PubMed2004

Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway.

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.

Aorta↗
PubMed2004

Vascular cell senescence and vascular aging.

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence". A number of genetic animal models carrying targeted disruption of the genes that confer the protection against senescence in vitro have been reported to exhibit the phenotypes of premature aging. Similar mutations have been found in the patients with premature aging syndromes. Many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. We have demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of pro-inflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Another line of evidence suggests that telomere-independent mechanisms are also involved in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. It is possible that mitogenic-signaling pathways induce telomere-dependent and telomere-independent senescence, which results in vascular dysfunction. Further understanding of the mechanism underlying cellular senescence will provide insights into the potential of antisenescence therapy for vascular aging.

Animals↗
PubMed2004

Usefulness of rapid quantitative measurement of myoglobin and troponin T in early diagnosis of acute myocardial infarction.

BACKGROUND: New equipment, the Cardiac Reader(TM), which can measure blood concentrations of troponin T (T) and myoglobin (M) in only 15 min at the bedside was evaluated for early diagnosis of acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 34 consecutive patients with AMI who came to hospital within 24 h after onset were studied. Blood samples were collected from the patients at admission and 6, 12, 24, 48 h after onset to qualitatively and quantitatively measure T, M and creatine kinase-MB fraction. There were 20 patients with positive results by qualitative troponin T test and 29 with positive results by quantitative test. Of the patients who visited hospital within 3 h of onset, 17% were positive by the qualitative test and 67% cases had positive results in the quantitative test. The patients were divided into 2 groups according to the flow grade in the infarct-related coronary artery. In the TIMI 0-1 group (n=28), serum myoglobin concentrations were higher than in the TIMI 3-4 group (n=6) at admission and at their peak. CONCLUSION: The rapid quantitative test of T and M is useful for early diagnosis of AMI and as an indicator of its severity, which can be evaluated from the myoglobin concentration in the hyper-acute phase.

Adult↗
PubMed2004

The role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular aging.

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." It has been reported that many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Introduction of telomere malfunction has been shown to lead to vascular dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against vascular dysfunction associated with senescence. Indeed, recent studies have demonstrated that telomere attrition occurs in the blood vessels and is associated with human atherosclerosis. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby, promotes vascular inflammation in vitro and in vivo. Although a causal link between vascular aging and vascular cell senescence remains elusive, a large body of data is consistent with cellular senescence contributing to age-associated vascular disorders. This review considers the clinical relevance of vascular cell senescence in vivo and discusses the potential of antisenescence therapy for human atherosclerosis.

Blood Vessels↗
PubMed2003

Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis.

BACKGROUND: Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis. METHODS AND RESULTS: We introduced an activated ras allele (H-rasV12) into human VSMCs using retroviral infection. Introduction of H-rasV12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated beta-galactosidase (SA-beta-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part through extracellular signal-regulated kinase activation. To determine whether Ras activation induces cellular senescence in vivo, we transduced the adenoviral vector encoding H-rasV12 into rat carotid arteries injured by a balloon catheter. Introduction of Ras into the arteries enhanced vascular inflammation and senescence compared with mock-infected injured arteries. Moreover, SA-beta-gal-positive VSMCs were detected in the intima of advanced human atherosclerotic lesions and exhibited increased levels of extracellular signal-regulated kinase activity and proinflammatory cytokine expression. CONCLUSIONS: Our results suggest that atherogenic stimuli mediated by Ras induce VSMC senescence and vascular inflammation, thereby contributing to atherogenesis. This novel mechanism of atherogenesis may provide insights into a new antisenescence treatment for atherosclerosis.

Adult↗