Masayuki Orimo
Chiba University
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Publication
Featured researches published by Masayuki Orimo.
Nature | 2007
Masanori Sano; Tohru Minamino; Haruhiro Toko; Hideyuki Miyauchi; Masayuki Orimo; Yingjie Qin; Hiroshi Akazawa; Kaoru Tateno; Yosuke Kayama; Mutsuo Harada; Ippei Shimizu; Takayuki Asahara; Hirofumi Hamada; Shuhei Tomita; Jeffrey D. Molkentin; Yunzeng Zou; Issei Komuro
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.
Circulation | 2006
Takeshige Kunieda; Tohru Minamino; Jun-ichiro Nishi; Kaoru Tateno; Tomomi Oyama; Taro Katsuno; Hideyuki Miyauchi; Masayuki Orimo; Sho Okada; Masayuki Takamura; Toshio Nagai; Shuichi Kaneko; Issei Komuro
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.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2009
Masayuki Orimo; Tohru Minamino; Hideyuki Miyauchi; Kaoru Tateno; Sho Okada; Junji Moriya; Issei Komuro
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+-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. Conclusions—These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.
Circulation Research | 2006
Takeshige Kunieda; Tohru Minamino; Taro Katsuno; Kaoru Tateno; Jun-ichiro Nishi; Hideyuki Miyauchi; Masayuki Orimo; Sho Okada; Issei Komuro
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.
Circulation Research | 2008
Junichiro Nishi; Tohru Minamino; Hideyuki Miyauchi; Aika Nojima; Kaoru Tateno; Sho Okada; Masayuki Orimo; Junji Moriya; Guo-Hua Fong; Kenji Sunagawa; Masabumi Shibuya; Issei Komuro
Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs “fine tuning” of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1+/− mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1+/− Akt1+/− mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.
Nature Medicine | 2009
Tohru Minamino; Masayuki Orimo; Ippei Shimizu; Takeshige Kunieda; Masataka Yokoyama; Takashi Ito; Aika Nojima; Akira Nabetani; Yuichi Oike; Hisahiro Matsubara; Fuyuki Ishikawa; Issei Komuro
Japanese Circulation Journal-english Edition | 2009
Masayuki Orimo; Tohru Minamino; Issei Komuro
Japanese Circulation Journal-english Edition | 2009
Junji Moriya; Tohru Minamino; Kaoru Tateno; Masayuki Orimo; Issei Komuro
Japanese Circulation Journal-english Edition | 2008
Masayuki Orimo; Tohru Minamino; Issei Komuro
Circulation | 2008
Junji Moriya; Tohru Minamino; Kaoru Tateno; Masayuki Orimo; Hideyuki Miyauchi; Sho Okada; Ippei Shimizu; Aika Nojima; Masataka Yokoyama; Issei Komuro