Seimi Satomi-Kobayashi

Kyoto Prefectural University of Medicine, Kyoto, Kyoto-fu, Japan

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Publications (12)69.7 Total impact

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    ABSTRACT: OBJECTIVE: Intimal thickening is considered to result from the dedifferentiation of medial smooth muscle cells (SMCs) from a contractile to a synthetic phenotype, and their subsequent migration and proliferation. It is unknown whether nectin-like molecule (Necl)-5, which is overexpressed in cancer cells, is involved in intimal thickening.Approach and Results-Necl-5 was upregulated in mouse carotid artery after ligation. Compared with wild-type mice, intimal thickening after carotid artery ligation was milder in Necl-5 knockout mice. In vitro, the expression levels of SMC differentiation markers were higher, whereas the expression level of an SMC dedifferentiation marker was lower, in Necl-5 knockout mouse aortic SMCs (MASMCs) compared with wild-type MASMCs. The migration, proliferation, and extracellular signal-regulated kinase activity in response to serum were decreased in Necl-5 knockout MASMCs compared with wild-type MASMCs. In wild-type MASMCs, inhibition of extracellular signal-regulated kinase activity increased the expression levels of SMC differentiation markers and decreased their migration and proliferation in response to serum. CONCLUSIONS: The present findings indicate that Necl-5 plays a role in the formation of intimal thickening after carotid artery ligation by regulating dedifferentiation, migration, and proliferation of SMCs in an extracellular signal-regulated kinase-dependent manner. Our results suggest that Necl-5 may represent a potential therapeutic target to limit intimal thickening after vascular injury.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2013; · 6.34 Impact Factor
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    ABSTRACT: Lipoprotein lipase has been considered as the only enzyme capable of generating lipid-derived fatty acids for cardiac energy. Endothelial lipase is another member of the triglyceride lipase family and hydrolyzes high-density lipoproteins. Although endothelial lipase is expressed in the heart, its function remains unclear. We assessed the role of endothelial lipase in the genesis of heart failure. Pressure overload-induced cardiac hypertrophy was generated in endothelial lipase-/- and wild-type mice by ascending aortic banding. Endothelial lipase expression in cardiac tissues was markedly elevated in the early phase of cardiac hypertrophy in wild-type mice, whereas lipoprotein lipase expression was significantly reduced. Endothelial lipase-/- mice showed more severe systolic dysfunction with left-ventricular dilatation compared with wild-type mice in response to pressure overload. The expression of mitochondrial fatty acid oxidation-related genes, such as carnitine palmitoyltransferase-1 and medium-chain acyl coenzyme A dehydrogenase, was significantly lower in the heart of endothelial lipase-/- mice than in wild-type mice. Also, endothelial lipase-/- mice had lower myocardial adenosine triphosphate levels than wild-type mice after aortic banding. In cultured cardiomyocytes, endothelial lipase was upregulated by inflammatory stimuli, whereas lipoprotein lipase was downregulated. Endothelial lipase-overexpression in cardiomyocytes resulted in an upregulation of fatty acid oxidation-related enzymes and intracellular adenosine triphosphate accumulation in the presence of high-density lipoprotein. Endothelial lipase may act as an alternative candidate to provide fatty acids to the heart and regulate cardiac function. This effect seemed relevant particularly in the diseased heart, where lipoprotein lipase action is downregulated.
    Hypertension 03/2013; · 6.87 Impact Factor
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    ABSTRACT: Differentiation of vascular smooth muscle cells (SMCs) into osteoblast-like cells is considered to be a mechanism of vascular calcification. However, regulators of osteoblast-like differentiation of vascular SMCs are not fully elucidated. Here, we investigated the expression of bone morphogenetic protein (BMP)-binding endothelial cell precursor-derived regulator (BMPER), a vertebrate homologue of Drosophila crossveinless-2, in vascular SMCs and the role and mode of action of BMPER in osteoblast-like differentiation of human coronary artery SMCs (HCASMCs). BMPER was expressed in cultured human vascular SMCs, including HCASMCs. Silencing of endogenous BMPER expression by an RNA interference technique inhibited osteoblast-like differentiation of HCASMCs, as evaluated by up-regulation of osteoblast markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), by down-regulation of a SMC marker α-smooth muscle actin (αSMA), and by mineralization. Treatment with recombinant BMPER enhanced, whereas BMP-2 reduced osteoblast-like differentiation. BMPER antagonized BMP-2-induced phosphorylation of Smad 1/5/8, suggesting that the effect of BMPER was mediated by antagonizing the action of BMP. BMPER increased IκBα phosphorylation and NF-κB activity and specific NF-κB decoy oligonucleotides deteriorated osteoblast-like differentiation of HCASMCs by BMPER. In human coronary artery with atherosclerotic plaque containing calcification, the BMPER-positive signals were observed in the neointimal and medial SMCs in the vicinity of the plaque. These findings indicate that BMPER is a novel regulator of the osteoblast-like differentiation of HCASMCs.
    Journal of Biological Chemistry 07/2012; 287(36):30336-45. · 4.65 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin α(V)β(3). However, how the interaction between VEGFR2 and integrin α(V)β(3) is regulated is not clear. To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin α(V)β(3), regulates the interaction between VEGFR2 and integrin α(V)β(3), and to clarify the role of Necl-5 in the VEGF-induced angiogenesis. Necl-5-knockout mice displayed no obvious defect in vascular development; however, recovery of blood flow after hindlimb ischemia and the VEGF-induced neovascularization in implanted Matrigel plugs were impaired in Necl-5-knockout mice. To clarify the mechanism of the regulation of angiogenesis by Necl-5, we investigated the roles of Necl-5 in the VEGF-induced angiogenic responses in vitro. Knockdown of Necl-5 by siRNAs in human umbilical vein endothelial cells (HUVECs) inhibited the VEGF-induced capillary-like network formation on Matrigel, migration, and proliferation, and conversely, enhanced apoptosis. Coimmunoprecipitation assays showed the interaction of Necl-5 with VEGFR2, and knockdown of Necl-5 prevented the VEGF-induced interaction of integrin α(V)β(3) with VEGFR2. Knockdown of Necl-5 suppressed the VEGFR2-mediated activation of downstream proangiogenic and survival signals, including Rap1, Akt, and endothelial nitric oxide synthase. These results demonstrate the critical role of Necl-5 in angiogenesis and suggest that Necl-5 may regulate the VEGF-induced angiogenesis by controlling the interaction of VEGFR2 with integrin α(v)β(3), and the VEGFR2-mediated Rap1-Akt signaling pathway.
    Circulation Research 03/2012; 110(5):716-26. · 11.86 Impact Factor
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    ABSTRACT: Angiogenesis contributes to physiological and pathological conditions, including atherosclerosis. The Rap1 small G protein regulates vascular integrity and angiogenesis. However, little is known about the effectors of Rap1 involved in angiogenesis. It is not known whether afadin, an adherens junction protein that connects immunoglobulin-like adhesion molecule nectins to the actin cytoskeleton and binds activated Rap1, plays a role in angiogenesis. We investigated the role of endothelial afadin in angiogenesis and attempted to clarify the underlying molecular mechanism. Treatment of human umbilical vein endothelial cells (HUVECs) with vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) induced the activation of Rap1. Activated Rap1 regulated intracellular localization of afadin. Knockdown of Rap1 or afadin by small interfering RNA inhibited the VEGF- and S1P-induced capillary-like network formation, migration, and proliferation, and increased the serum deprivation-induced apoptosis of HUVECs. Knockdown of Rap1 or afadin decreased the accumulation of adherens and tight junction proteins to the cell-cell contact sites. Rap1 regulated the interaction between afadin and phosphatidylinositol 3-kinase (PI3K), recruitment of the afadin-PI3K complex to the leading edge, and the activation of Akt, indicating the involvement of Rap1 and afadin in the PI3K-Akt signaling pathway. Binding of afadin to Rap1 regulated the activity of Rap1 in a positive-feedback manner. In vivo, conditional deletion of afadin in mouse vascular endothelium using a Cre-loxP system impaired the VEGF- and S1P-induced angiogenesis. These results demonstrate a novel molecular mechanism by which Rap1 and afadin regulate the VEGF- and S1P-induced angiogenesis.
    Circulation Research 04/2010; 106(11):1731-42. · 11.86 Impact Factor
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    ABSTRACT: The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca(2+)-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload-induced cardiac dysfunction.
    Hypertension 09/2009; 54(4):825-31. · 6.87 Impact Factor
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    ABSTRACT: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients with multiple coronary risk factors. There was a positive relationship between FMD and plasma BH4 levels and a negative relationship between FMD and plasma BH2 levels. Subsequently, a strong positive relationship between FMD and the BH4/BH2 ratio (r=0.585, P<0.0001) was found. Although we did not find any significant relationship between pteridine levels and individual traditional risk factors, the BH4/BH2 ratio in patients with more than 2 risk factors showed significant reductions compared with that in those without risk factors. Statin treatment improved FMD in association with an increase in the plasma BH4/BH2 ratio. Plasma pteridine levels were associated with endothelial dysfunction in cardiovascular disorders.
    Circulation Journal 03/2009; 73(5):955-62. · 3.58 Impact Factor
  • Circulation Journal - CIRC J. 01/2009; 73(5):955-962.
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    ABSTRACT: Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function was preserved compared with the control MI rats. The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function.
    Circulation Journal 10/2008; 72(9):1512-9. · 3.58 Impact Factor
  • Circulation Journal - CIRC J. 01/2008; 72(9):1512-1519.
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    ABSTRACT: We investigated whether autologous transplantation of skeletal myoblasts (MB) transferred with cardiotrophin-1 (CT-1) gene could retard the transition to heart failure (HF) in Dahl salt-sensitive (DS) hypertensive rats. Although MB is a therapeutic candidate for chronic HF, little is known about the efficiency of this strategy when applied in nonischemic HF. Cardiotrophin-1 has potent hypertrophic and survival effects on cardiac myocytes. We hypothesized that transplantation of CT-1-expressing myoblasts could provide cardioprotective effects against ventricular remodeling in DS hypertensive rats. The DS rats were fed a high salt diet for 6 weeks and developed left ventricular (LV) hypertrophy at 11 weeks. At this stage, animals underwent MB to the myocardium with skeletal myoblasts transferred with CT-1 gene using retrovirus (transplantation of CT-1-expressing myoblasts [MB + CT], n = 31) or myoblasts alone (MB, n = 31). The sham group rats were injected with phosphate-buffered saline (n = 24). At 17 weeks, MB and MB + CT groups showed a significant alleviation of LV dilation and contractile dysfunction compared with the sham group. The degree of alleviation was significantly greater in the MB + CT group than the MB group (LV end-diastolic dimension: sham 7.06 +/- 0.14 mm, MB 6.51 +/- 0.16 mm, MB + CT 6.24 +/- 0.07 mm; fractional shortening: sham 32.1 +/- 1.4%, MB 38.5 +/- 1.5%, MB + CT 43.2 +/- 0.8%). Histological examination revealed that the myocyte size was 20% larger in the MB + CT group at 17 weeks than in the age-matched sham group. Upregulation of renin-angiotensin and endothelin systems during the transition to HF was attenuated by myoblast transplantation, and this effect was enhanced in the MB + CT group. Transplantation of skeletal myoblasts combined with CT-1-gene transfer could be a useful therapeutic strategy for HF.
    Journal of the American College of Cardiology 07/2004; 43(12):2337-47. · 14.09 Impact Factor
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    ABSTRACT: It is generally believed that the cardiac myocytes withdraw from the cell cycle shortly after birth and thereafter any loss of myocardial tissue cannot be repaired. However, recent reports indicate that cardiac myocytes can be regenerated by stem cells derived from bone marrow in the damaged hearts. In this study, we investigated whether bone marrow-derived cells can differentiate into cardiac myocytes in the intact hearts. We performed bone marrow transplantation from syngenic male mice to female c57/B6 mice. In female mice's hearts, the presence of cells from male mice was examined by FISH method that detects Y chromosome. Using the same samples, we also performed immunohistochemical staining with muscle specific antibodies. In the heart sections of female mice, there were some cells that were considered as differentiated myocytes derived from male bone marrow (0.01~0.09% of total myocytes) and the proportion of the cells increased as the period after bone marrow transplantation became longer (3 months after vs. 8 months after). These results suggest that, not only in the damaged heart but also in the intact heart, a portion of cardiac myocytes is recruited by bone marrow-derived cells.
    The Kobe journal of medical sciences 01/2003; 48(5-6):161-6.