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Sho Okada,
Masataka Yokoyama,
Haruhiro Toko,
Kaoru Tateno,
Junji Moriya,
Ippei Shimizu, Aika Nojima,
Takashi Ito,
Yohko Yoshida,
Yoshio Kobayashi,
Hideki Katagiri,
Tohru Minamino,
Issei Komuro
[show abstract]
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ABSTRACT: The central nervous system is thought to influence the regulation of the cardiovascular system in response to humoral and neural signals from peripheral tissues, but our understanding of the molecular mechanisms involved is still quite limited.
Here, we demonstrate a central nervous system-mediated mechanism by which brain-derived neurotrophic factor (BDNF) has a protective effect against cardiac remodeling after myocardial infarction (MI). We generated conditional BDNF knockout mice, in which expression of BDNF was systemically reduced, by using the inducible Cre-loxP system. Two weeks after MI was induced surgically in these mice, systolic function was significantly impaired and cardiac size was markedly increased in conditional BDNF knockout mice compared with controls. Cardiomyocyte death was increased in these mice, along with decreased expression of survival molecules. Deletion of the BDNF receptor (tropomyosin-related kinase B) from the heart also led to the exacerbation of cardiac dysfunction after MI. The plasma levels of BDNF were markedly increased after MI, and this increase was associated with the upregulation of BDNF expression in the brain, but not in the heart. Ablation of afferent nerves from the heart or genetic disruption of neuronal BDNF expression inhibited the increase of plasma BDNF after MI and led to the exacerbation of cardiac dysfunction. Peripheral administration of BDNF significantly restored the cardiac phenotype of neuronal BDNF-deficient mice.
These results suggest that BDNF expression is upregulated by neural signals from the heart after MI and then protects the myocardium against ischemic injury.
Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(8):1902-9. · 6.37 Impact Factor
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Ippei Shimizu,
Yohko Yoshida,
Taro Katsuno,
Kaoru Tateno,
Sho Okada,
Junji Moriya,
Masataka Yokoyama, Aika Nojima,
Takashi Ito,
Rudolf Zechner,
Issei Komuro,
Yoshio Kobayashi,
Tohru Minamino
[show abstract]
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ABSTRACT: Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.
Cell metabolism 01/2012; 15(1):51-64. · 17.35 Impact Factor
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Ippei Shimizu,
Tohru Minamino,
Haruhiro Toko,
Sho Okada,
Hiroyuki Ikeda,
Noritaka Yasuda,
Kaoru Tateno,
Junji Moriya,
Masataka Yokoyama, Aika Nojima,
Gou Young Koh,
Hiroshi Akazawa,
Ichiro Shiojima,
C Ronald Kahn,
E Dale Abel,
Issei Komuro
[show abstract]
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ABSTRACT: 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 overload-induced 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.
The Journal of clinical investigation 05/2010; 120(5):1506-14. · 15.39 Impact Factor
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Junji Moriya,
Tohru Minamino,
Kaoru Tateno,
Sho Okada,
Akiyoshi Uemura,
Ippei Shimizu,
Masataka Yokoyama, Aika Nojima,
Mitsuhiro Okada,
Hisashi Koga,
Issei Komuro
[show abstract]
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ABSTRACT: The axon-guiding molecules known as semaphorins and their receptors (plexins) regulate the vascular pattern and play an important role in the development of vascular network during embryogenesis. Semaphorin (Sema)3E is one of the class 3 semaphorins, and plexinD1 is known to be its receptor. Although these molecules have a role in embryonic vascular development, it remains unclear whether the Sema3E/plexinD1 axis is involved in postnatal angiogenesis.
The objective of this study was to elucidate the role of Sema3E/plexinD1 in postnatal angiogenesis.
Sema3E inhibited cell growth and tube formation by suppressing the vascular endothelial growth factor (VEGF) signaling pathway. Expression of Sema3E and plexinD1 was markedly upregulated in ischemic limbs of mice (2.5- and 4.5-fold increase for Sema3E and plexinD1, respectively), and inhibition of this pathway by introduction of the plexinD1-Fc gene or disruption of Sema3E led to a significant increase of blood flow recovery (1.6- and 1.5-fold increase for the plexinD1-Fc gene treatment and Sema3E disruption, respectively). Hypoxia activated the tumor suppressor protein p53, thereby upregulating Sema3E expression. Expression of p53 and Sema3E was enhanced in diabetic mice compared with normal mice (2- and 1.3-fold increase for p53 and Sema3E, respectively). Consequently, neovascularization after VEGF treatment was poor in the ischemic tissues of diabetic mice, whereas treatment with VEGF plus plexinD1-Fc markedly improved neovascularization.
These results indicate that inhibition of Sema3E may be a novel strategy for therapeutic angiogenesis, especially when VEGF is ineffective.
Circulation Research 11/2009; 106(2):391-8. · 9.49 Impact Factor
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Tohru Minamino,
Masayuki Orimo,
Ippei Shimizu,
Takeshige Kunieda,
Masataka Yokoyama,
Takashi Ito, Aika Nojima,
Akira Nabetani,
Yuichi Oike,
Hisahiro Matsubara,
Fuyuki Ishikawa,
Issei Komuro
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ABSTRACT: 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).
Nature medicine 10/2009; 15(9):1082-7. · 27.14 Impact Factor
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Yosuke Kayama,
Tohru Minamino,
Haruhiro Toko,
Masaya Sakamoto,
Ippei Shimizu,
Hidehisa Takahashi,
Sho Okada,
Kaoru Tateno,
Junji Moriya,
Masataka Yokoyama, Aika Nojima,
Michihiro Yoshimura,
Kensuke Egashira,
Hiroyuki Aburatani,
Issei Komuro
[show abstract]
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ABSTRACT: To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.
Journal of Experimental Medicine 07/2009; 206(7):1565-74. · 13.85 Impact Factor
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Jun-ichiro Nishi,
Tohru Minamino,
Hideyuki Miyauchi, Aika Nojima,
Kaoru Tateno,
Sho Okada,
Masayuki Orimo,
Junji Moriya,
Guo-Hua Fong,
Kenji Sunagawa,
Masabumi Shibuya,
Issei Komuro
[show abstract]
[hide abstract]
ABSTRACT: 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.
Circulation Research 07/2008; 103(3):261-8. · 9.49 Impact Factor
