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S Sasayama

Publications and source records attributed to S Sasayama.

At least 109 records · Page 6Linked to original sources
PubMed2000

[Idiopathic cardiomyopathy--pathogenesis].

Etiology of hypertrophic cardiomyopathy and dilated cardiomyopathy has been thought to be different. In fact, most of the mutations of the genes of sarcomere were shown to be associated with hypertrophic cardiomyopathy. However, the same mutations of the genes such as mitochondria, dystrophin or actin have been reported in both the patients with hypertrophic and dilated cardiomyopathy. Recently, the importance of hepatitis C virus infection was noted in patients with cardiomyopathy, and the virus may also cause both hypertrophic and dilated cardiomyopathy. Therefore, the unknown factors may define the phenotype of cardiomyopathy. Increased expression of cytokines and nitric oxide has been shown and is being increasing recognized as important factors in the pathogenesis of cardiomyopathy.

Actins↗
PubMed2000

[Arrhythmias].

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Arrhythmias, Cardiac↗
PubMed1999

p300 protein as a coactivator of GATA-5 in the transcription of cardiac-restricted atrial natriuretic factor gene.

A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator and a negative regulator of cellular proliferation. A previous study suggests that the p300 family is also involved in cell type-specific transcription in cardiac myocytes. However, nothing is known about which cardiac transcription factor(s) interact with and transactivate through these proteins. The transcription factors GATA-4/5/6 have been implicated as key regulators of cardiogenesis, and they participate in the transcription of many cardiac-specific genes. Here we show that E1A represses the GATA-5-dependent transactivation of a promoter derived from the cardiac-restricted atrial natriuretic factor gene. This repression is correlated with the interaction of E1A with p300, indicating that p300 participates in GATA-5-dependent transactivation. E1A markedly down-regulates endogenous atrial natriuretic factor expression, as well as disrupts the interaction between p300 and GATA-5. A small fragment of p300 containing the carboxyl-terminal cysteine/histidine-rich domain, sufficient to interact with GATA-5, prevents transcriptional activation by GATA-5 as a dominant-negative mutant. Consistent with its role as a coactivator, p300 markedly potentiates GATA-5-activated transcription. These results implicate p300 as an important component of myocardial cell differentiation and provide an insight into the relationship between mechanisms that mediate cell type-specific transcription and cell cycle regulation during cardiogenesis.

3T3 Cells↗
PubMed1999

Contribution of endothelin-1 to myocardial injury in a murine model of myocarditis: acute effects of bosentan, an endothelin receptor antagonist.

BACKGROUND: Endothelin (ET) is one of the most important contributing factors in the pathophysiology of cardiovascular diseases. However, little is known about its role in myocarditis. METHODS AND RESULTS: Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus. Expression levels of ET-converting enzyme-1 (ECE-1) and prepro-ET-1 mRNA were significantly increased at 7 and 14 days after virus inoculation. Plasma and myocardial ET-1 levels were significantly higher in infected than noninfected mice between 5 and 14 days after virus inoculation. Immunohistochemical analyses revealed that not only endothelial cells and myocytes but also infiltrating mononuclear cells produced ET-1 protein at 7 days. Oral bosentan, a mixed ET-1 receptor antagonist, was administered after virus inoculation in doses of 0 (control group), 10, or 100 mg. kg(-1). d(-1), and the animals were killed on day 14. Mean heart weight/body weight ratios were 8.3+/-1.8 versus 11.2+/-2.4 versus 10. 8+/-2.4 in the bosentan 100 mg. kg(-1). d(-1) versus 10 mg. kg(-1). d(-1) versus control groups, respectively (P<0.05). Corresponding histological scores for myocardial necrosis were 2.0+/-0.2 versus 2. 9+/-0.3 versus 3.0+/-0.4 (P<0.05), and cellular infiltration scores were 2.3+/-0.3 versus 2.9+/-0.4 versus 3.3+/-0.4 (P<0.05). Animals killed on day 5 had significantly smaller necrotic areas after treatment with bosentan 100 mg. kg(-1). d(-1) than the group treated with a lower dose or the control group, despite the absence of differences in virus titers. CONCLUSIONS: This study suggests that ET-1 plays an important pathophysiological role in viral myocarditis. Treatment with bosentan had a cardioprotective effect without modifying viral replication.

Animals↗
PubMed1999

Mast cells cause apoptosis of cardiomyocytes and proliferation of other intramyocardial cells in vitro.

BACKGROUND: Mast cells are multifunctional cells containing various mediators such as cytokines, proteases, and histamine. They are found in the human heart and have been implicated in ventricular hypertrophy and heart failure. However, their roles in pathogenesis of these diseases are unknown. METHODS AND RESULTS: Cultured cardiomyocytes from neonatal rats were incubated with mast cell granules (MCGs) for 24 hours. The highest concentration of diluted MCGs caused the death of approximately 70% of cardiomyocytes. This cell death was proved to be apoptosis, as quantified by electron microscopy and biochemical criteria. MCG-mediated cytotoxicity was prevented by pretreatment of MCGs with protease inhibitors or a neutralizing antibody against rat mast cell chymase 1 (RMCP 1). RMCP 1 by itself was proved to induce cell death of cardiomyocytes. These results suggest that RMCP 1 contained in MCGs causes the death of cardiomyocytes. In contrast, MCGs induced the proliferation of intramyocardial cells other than myocytes. RMCP 1 was also proved to induce their proliferation. CONCLUSIONS: Mast cells cause apoptosis of cardiomyocytes and proliferation of other intramyocardial cells via the activity of RMCP 1. Our results suggest that mast cell chymase may play a role in the progression of heart failure, because loss of cardiomyocytes and proliferation of nonmyocardial cells exaggerate its pathophysiology.

Animals↗
PubMed1999

FTY720, a new immunosuppressant, promotes long-term graft survival and inhibits the progression of graft coronary artery disease in a murine model of cardiac transplantation.

Background-Effective immunosuppression is a critical determinant of organ and patient survival in cardiac transplantation. The present study was designed to determine the potency of FTY720, a new synthesized immunosuppressant, and examine its clinical potential as an immunosuppressant. Methods and Results-Hearts of DBA/2 mice were transplanted heterotopically in C57BL/6 mice. Recipients were treated with oral FTY720 in doses of 0.3, 1, 3, or 10 mg. kg(-1). d(-1) or with 40 mg. kg(-1). d(-1) of cyclosporin A (CsA) as a comparative treatment. The median graft survival time (MST) was significantly prolonged by treatment with FTY720 10 mg. kg(-1). d(-1). MST was not prolonged by FTY720 1 mg. kg(-1). d(-1) or CsA. However, FTY720 1 mg. kg(-1). d(-1) combined with CsA 40 mg. kg(-1). d(-1) resulted in a significant prolongation of MST. Histopathological studies performed 5 days after transplantation demonstrated remarkable suppression of inflammatory response by treatment with FTY720 10 mg. kg(-1). d(-1). Interleukin (IL)-2 and interferon (IFN)-gamma production was not suppressed; however, cytotoxic T lymphocyte activity was strongly suppressed in vitro. In addition, IL-2-stimulated T-cell proliferation and class I and class II MHC antigen expression on IFN-gamma-stimulated macrophages were strongly inhibited by FTY720. Histopathological studies 60 days after transplantation (DBA/2-B10.D2) demonstrated a beneficial effect on graft atherosclerosis. Conclusions-FTY720 promoted long-term cardiac graft survival and strongly inhibited the progression of graft atherosclerosis. These observations suggest that FTY720 has a promising clinical potential in cardiac transplantation.

Animals↗
PubMed1999

Treatment of experimental viral myocarditis with interleukin-10.

BACKGROUND: The T helper cell type 2-associated cytokine interleukin (IL)-10 has a variety of immunomodulatory properties. However, the effects of the cytokine on viral myocarditis remain unclear. METHODS AND RESULTS: We studied the effects of recombinant human IL-10 (rhIL-10) fully active on mouse cells in a murine experimental model of acute viral myocarditis caused by the encephalomyocarditis virus (EMCV). Four-week-old DBA/2 mice were inoculated with EMCV (day 0). rhIL-10 (10 microg/mouse) was administered once daily, starting on day 0, and control mice received vehicle only. Survival rates were determined on day 14. Myocardial histopathology, cytokine levels in the heart by ELISA assay, and myocardial virus concentration were examined on day 6, and the expression levels of myocardial inducible nitric oxide synthase (iNOS) mRNA were measured by competitive polymerase chain reaction. The 14-day survival in mice treated with rhIL-10 was significantly higher (80%) than in the control group (30%, n=10 in each, P<0.05). rhIL-10 treatment significantly attenuated myocardial lesions and suppressed tumor necrosis factor-alpha and IL-2 in the heart. rhIL-10 treatment had little effect on myocardial virus concentration. The expression levels of myocardial iNOS mRNA were significantly decreased in the group treated with rhIL-10 (8.6+/-4.7 amol/mg total RNA in treated versus 26.5+/-7.1 amol/mg total RNA in control mice, P<0.05). CONCLUSIONS: These findings provide new insights into the in vivo effects of IL-10 on viral infection and suggest a therapeutic effect of IL-10 on viral myocarditis.

Animals↗
PubMed1999

DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries.

We have identified and characterized mouse, rat, and human cDNAs that encode a novel secreted protein of 448 amino acids named DANCE (developmental arteries and neural crest epidermal growth factor (EGF)-like). DANCE contains six calcium-binding EGF-like domains, one of which includes an RGD motif. Overexpression studies of recombinant DANCE protein document that DANCE is a secreted 66-kDa protein. DANCE and recently described protein S1-5 comprise a new EGF-like protein family. The human DANCE gene was mapped at chromosome 14q32.1. DANCE mRNA is mainly expressed in heart, ovary, and colon in adult human tissues. Expression profile analysis by in situ hybridization revealed prominent DANCE expression in developing arteries. DANCE is also expressed in neural crest cell derivatives, endocardial cushion tissue, and several other mesenchymal tissues. In adult vessels, DANCE expression is largely diminished but is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells that lose their ability to proliferate in late stage of injury. DANCE protein was shown to promote adhesion of endothelial cells through interaction of integrins and the RGD motif of DANCE. DANCE is thus a novel vascular ligand for integrin receptors and may play a role in vascular development and remodeling.

Amino Acid Sequence↗
PubMed1999

Heparin potentiates collateral growth but not growth of intramyocardial endarteries in dogs with repeated coronary occlusion.

Heparin accelerates coronary collateral development in various animal models of myocardial ischemia. The purpose of this study was to clarify the beneficial effect of heparin on canine collateral development. Seventeen adult mongrel dogs were instrumented for measurements of a subendocardial segment length in the central area perfused by the left circumflex coronary artery, its flow, and left ventricular pressure. A pulsed Doppler flow probe and an externally inflatable pneumatic occluder were placed around the proximal circumflex artery. After the recovery from surgery, 2-min circumflex coronary artery occlusions were repeated eight times at 58-min intervals daily. After excluding seven dogs with well-developed preexisting collateral circulation, ten dogs were randomized into two groups with (n = 5) and without (n = 5) heparin treatment. The total occlusion time until adequate collateral development (an index of collateral growth) was 164+/-34 (SD) min in dogs with heparin treatment, being significantly less than 289+/-49 min in dogs without heparin (p<0.01). In contrast, the extent of the reduction in resting blood flow of the repeatedly occluded circumflex artery (an index of neovascularization toward the ischemic area) was comparable in dogs with and without heparin (15.4+/-12.4% vs. 21.1+/-13.6%, p=NS). Heparin promotes nonsprouting angiogenesis (arteriogenesis) of preformed collateral vessels but not neovascularization toward the ischemic area in dogs with brief repetitive coronary occlusions.

Animals↗
PubMed1999

alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes.

BACKGROUND: The apoptosis of cardiac myocytes may play a role in the development of heart failure. Norepinephrine is one of the factors activated in heart failure and can induce myocardial cell apoptosis in culture. However, it is unknown if alpha- and beta-adrenergic pathways coordinately or differentially regulate apoptosis and if this apoptotic pathway uses common or cell type-specific apoptotic signals. METHODS AND RESULTS: We stimulated cultured neonatal rat cardiac myocytes with an alpha(1)-adrenergic agonist (PE, phenylephrine), a beta-adrenergic agonist (isoproterenol [Iso]) or a membrane-permeable cAMP analogue (8-Br-cAMP) in serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly increased the number of TUNEL-positive cells (%TUNEL-positive nuclei >40%) compared with saline stimulation (<10%). DNA fragmentation was also confirmed by ladder formation in agarose gels. Apoptotic myocytes were characterized by cell shrinkage and nuclear condensation, consistent with morphological features of apoptosis. The Iso-induced apoptosis was almost completely inhibited by the protein kinase A-specific inhibitor KT5720. In contrast, PE inhibited 8-Br-cAMP-induced myocardial cell apoptosis. The apoptosis-inhibitory effect by PE was negated by the alpha(1)-adrenergic receptor antagonist prazosin and the MEK-1-specific inhibitor PD098059. Interestingly, although 8-Br-cAMP markedly induced apoptosis in cardiac myocytes, it completely blocked serum depletion-induced apoptosis in PC12 cells, a rat pheochromocytoma cell line. CONCLUSIONS: These findings indicate that alpha- and beta-adrenergic pathways differentially regulate myocardial cell apoptosis. The results also suggest that a cAMP- protein kinase A pathway is necessary and sufficient for beta-adrenergic agonist-induced apoptosis and that this apoptotic pathway is not functional in other cell types, for example, PC12 cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

GATA-5 is involved in leukemia inhibitory factor-responsive transcription of the beta-myosin heavy chain gene in cardiac myocytes.

Leukemia inhibitory factor is a member of a family of structurally related cytokines sharing the receptor component gp130. Activation of gp130 by leukemia inhibitory factor is sufficient to induce myocardial cell hypertrophy accompanied by specific changes in the pattern of gene expression. However, the molecular mechanisms that link gp130 activation to these changes have not been clarified. The present study investigated the transcriptional pathways by which leukemia inhibitory factor activates beta-myosin heavy chain expression during myocardial cell hypertrophy. Mutation of the GATA motif in the beta-myosin heavy chain promoter totally abolished leukemia inhibitory factor-responsive transcription without changing basal transcriptional activity. In contrast, endothelin-1 responsiveness was unaffected by the GATA mutation. Among members of the cardiac GATA transcription factor subfamily (GATA-4, -5, and -6), GATA-5 was the sole and potent transactivator for the beta-myosin heavy chain promoter. This transactivation was dependent on sequence-specific binding of GATA-5 to the beta-myosin heavy chain GATA element. Cardiac nuclear factors that bind to to the beta-myosin heavy chain GATA element were induced by leukemia inhibitory factor stimulation. Last, leukemia inhibitory factor stimulation markedly increased transcripts of cardiac GATA-5, the expression of which is normally restricted to the early embryo. Thus, GATA-5 may be involved in gp130 signaling in cardiac myocytes.

Animals↗
PubMed1999

Tissue factor pathway inhibitor-2 is a novel mitogen for vascular smooth muscle cells.

A mitogen for growth-arrested cultured bovine aortic smooth muscle cells was purified to homogeneity from the supernatant of cultured human umbilical vein endothelial cells by heparin affinity chromatography and reverse-phase high performance liquid chromatography. This mitogen was revealed to be tissue factor pathway inhibitor-2 (TFPI-2), which is a Kunitz-type serine protease inhibitor. TFPI-2 was expressed in baby hamster kidney cells using a mammalian expression vector. Recombinant TFPI-2 (rTFPI-2) stimulated DNA synthesis and cell proliferation in a dose-dependent manner (1-500 nM). rTFPI-2 activated mitogen-activated protein kinase (MAPK) activity and stimulated early proto-oncogene c-fos mRNA expression in smooth muscle cells. MAPK, c-fos expression and the mitogenic activity were inhibited by a specific inhibitor of MAPK kinase, PD098059. Thus, the mitogenic function of rTFPI-2 is considered to be mediated through MAPK pathway. TFPI has been reported to exhibit antiproliferative action after vascular smooth muscle injury in addition to the ability to inhibit activation of the extrinsic coagulation cascade. However, structurally similar TFPI-2 was found to have a mitogenic activity for the smooth muscle cell.

Animals↗
PubMed1999

Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries.

Monocyte chemoattractant protein-1 (MCP-1)/monocyte chemotactic and activating factor (MCAF) has been suggested to promote atherogenesis. The effects of in vivo neutralization of MCP-1 in a rat model were examined in an effort to clarify the role of MCP-1 in the development of neointimal hyperplasia. Competitive polymerase chain reaction analysis revealed maximum MCP-1 mRNA expression at 4 hours after carotid arterial injury. Increased immunoreactivities of MCP-1 were also detected at 2 and 8 hours after injury. Either anti-MCP-1 antibody or nonimmunized goat IgG (10 mg/kg) was then administered every 12 hours to rats that had undergone carotid arterial injury. Treatment with 3 consecutive doses of anti-MCP-1 antibody within 24 hours (experiment 1) and every 12 hours for 5 days (experiment 2) significantly inhibited neointimal hyperplasia at day 14, resulting in a 27.8% reduction of the mean intima/media ratio (P<0.05) in experiment 1 and a 43.6% reduction (P<0.01) in experiment 2. This effect was still apparent at day 56 (55.6% inhibition; P<0.05). The number of vascular smooth muscle cells in the neointima at day 4 was significantly reduced by anti-MCP-1 treatment, demonstrating the important role of MCP-1 in early neointimal lesion formation. However, recombinant MCP-1 did not stimulate chemotaxis of vascular smooth muscle cells in an in vitro migration assay. These results suggest that MCP-1 promotes neointimal hyperplasia in early neointimal lesion formation and that neutralization of MCP-1 before, and immediately after, arterial injury may be effective in preventing restenosis after angioplasty. Further studies are needed to clarify the mechanism underlying the promotion of neointimal hyperplasia by MCP-1.

Animals↗