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Nobuo Sakamoto,
Yasuto Hoshino,
Tomofumi Misaka,
Hiroyuki Mizukami,
Satoshi Suzuki,
Koichi Sugimoto,
Takayoshi Yamaki,
Hiroyuki Kunii,
Kazuhiko Nakazato,
Hitoshi Suzuki,
Shu-Ichi Saitoh,
Yasuchika Takeishi
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ABSTRACT: Tenascin-C, a large oligometric glycoprotein of the extracellular matrix, increases the expression of matrix metalloproteinases that lead to plaque instability and rupture, resulting in acute coronary syndrome (ACS). We hypothesized that a high serum tenascin-C level is associated with plaque rupture in patients with ACS. Fifty-two consecutive ACS patients who underwent emergency percutaneous coronary intervention (PCI) and, as a control, 66 consecutive patients with stable angina pectoris (SAP) were enrolled in this study. Blood samples were obtained from the ascending aorta just prior to the PCI procedures. After coronary guide-wire crossing, intravascular ultrasonography (IVUS) was performed for assessment of plaque characterization. Based on the IVUS findings, ACS patients were assigned to two groups according to whether there was ruptured plaque (ruptured ACS group) or not (nonruptured ACS group). There were 23 patients in the ruptured group and 29 patients in the nonruptured group. Clinical characteristics and IVUS measurements did not differ between the two groups. Tenascin-C levels were significantly higher in the ruptured ACS group than in the SAP group, whereas there was no significant difference between the nonruptured ACS and SAP groups. Importantly, in the ruptured ACS group, tenascin-C levels were significantly higher than in the nonruptured ACS group (71.9 ± 34.9 vs 50.5 ± 20.5 ng/ml, P < 0.005). Our data demonstrate that tenascin-C level is associated with pathologic conditions in ACS, especially the presence of ruptured plaque.
Heart and Vessels 03/2013; · 2.05 Impact Factor
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ABSTRACT: A 57-year-old male with end stage renal disease underwent coronary angiography (CAG). The CAG revealed two vessel disease with severe calcification. A week after the percutaneous coronary intervention (PCI) to the left anterior descending coronary artery (LAD), we performed PCI to the right coronary artery (RCA). Because of the calcification, no devices could be crossed. We then performed 5 in 7 method using Heartrail ST01, and inserted it across the stenosis, with dilatation balloon at the distal RCA as anchoring. Finally we managed to implant two stents. We report that 5 in 7 method and deep seating of 5 Fr. guiding catheter were effective for the severely calcified lesion.
Cardiovascular intervention and therapeutics. 08/2012;
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ABSTRACT: Drug-eluting stent (DES) dramatically reduces the incidence of restenosis and rates of target lesion revascularization. Although
several reports suggest that very late stent thrombosis could occur in patients after DES implantation, neointimal plaque
rupture may be uncommon in the patients treated with DES compared with bare-metal stent. It is unclear that the reason why
the patient in acute coronary syndrome (ACS) treated with DES has a high frequency of very late stent thrombosis and pathophysiological
mechanisms of neointimal plaque rupture after DES implantation. We report a case of very late stent thrombosis with the findings
of neontimal plaque rupture as well as incomplete stent apposition 4years after sirolimus-eluting stent implantation in ACS.
KeywordsSirolimus-eluting stent (SES)–Intravascular ultrasound (IVUS)–Very late stent thrombosis–Incomplete stent apposition (ISA)–Neointimal plaque rupture
Cardiovascular Intervention and Therapeutics 04/2012; 26(3):263-268.
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Nobuo Sakamoto,
Shoji Iwaya,
Takashi Owada,
Yuichi Nakamura,
Hiroyuki Yamauchi,
Yasuto Hoshino,
Hiroyuki Mizukami,
Koichi Sugimoto,
Takayoshi Yamaki,
Hiroyuki Kunii,
Kazuhiko Nakazato,
Hitoshi Suzuki,
Shu-Ichi Saitoh,
Yasuchika Takeishi
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ABSTRACT: Background: Coronary flow reserve (CFR) provides essential information about the coronary microvasculature. Chronic kidney disease (CKD) is a risk factor for cardio-cerebrovascular diseases. We hypothesized that low CFR is associated with CKD and long-term cardio-cerebrovascular events in the patients without obstructive coronary artery diseases and vasospasm.Method and Results: In this study, 73 patients suspected with coronary artery disease but had no epicardial coronary stenosis and vasospasm were enrolled. There were 13 CKD patients and CFR was measured using the Doppler flow wire methods in the left anterior descending artery. CFR was significantly lower in CKD group than non-CKD group (3.13±0.6 vs. 4.00±1.1, P=0.007). From multivariate logistic regression analysis, the independent factor associated with the presence of CKD was only CFR (odds ratio 3.85, 95% confidence interval 1.27-11.70, P=0.017). In the patients with low CFR (≤ 2.8), cardio-cerebrovascular events were more common than those with normal CFR (CFR > 2.8). Besides, in the patients who had both low CFR and CKD, long-term cardio-cerebrovascular events were more likely to occur than those with normal CFR or non-CKD.Conclusions: Our data suggest that low CFR is associated with CKD and cardio-cerebrovascular events in the patients without coronary stenosis and vasospasm.
Fukushima journal of medical science 01/2012; 58(2):136-43.
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Akihiko Sato, Nobuo Sakamoto,
Katsuya Ando,
Takashi Kaneshiro,
Hironori Uekita,
Koichi Sugimoto,
Takayoshi Yamaki,
Hiroyuki Kunii,
Kazuhiko Nakazato,
Hitoshi Suzuki,
Shu-Ichi Saitoh,
Masatomo Sato,
Kazuaki Tamagawa,
Takuro Arimura,
Akinori Kimura,
Yasuchika Takeishi
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ABSTRACT: We herein report the case of a 61-year-old woman with dilated phase of hypertrophic cardiomyopathy (D-HCM) who had been diagnosed with HCM 17 years previously. On admission, her left ventricle (LV) had marked dilation, dyssynchrony with diffuse severe hypokinesis, and ventricular tachycardia. She had two mutations in the cardiac myosin binding protein-C gene, which were suspected to be the causes of the D-HCM. We performed LV reconstruction surgery and cardiac resynchronization therapy with a defibrillator for her drug-resistant severe heart failure. After surgery, her New York Heart Association class dramatically improved, and she has not been re-hospitalized since these treatments.
Internal Medicine 01/2012; 51(18):2559-64. · 0.94 Impact Factor
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ABSTRACT: Coronary pressure-derived fractional flow reserve (FFR) has been used to evaluate functional severity of coronary artery stenoses. The cut-off point of 0.75 was considered to be the indication for percutaneous coronary intervention (PCI). In this study, we examined the prognosis of patients in whom PCI was deferred because the lesion was not significant by FFR (≥0.75). We measured FFR of 44 patients (50 lesions with angiographically intermediate stenoses by pressure wire between 2002 and 2009. Out of 44 patients (50 lesions), functionally non-significant stenoses with FFR≥0.75 were 29 patients (33 lesions) and PCI was deferred. In the remaining 15 patients (17 lesions), FFR was <0.75 and PCI was performed. Patients were followed up for an average period of 53 months with endpoints of major adverse cardiac events (MACE; cardiac death, acute coronary syndrome, PCI, and coronary artery bypass grafting). The rate of MACE was 2/29 (6.9%) in patients with FFR≥0.75 and 2/15 (13.3%) in those with FFR<0.75, and it was not statistically different between the two groups. Since long-term clinical outcomes after deferral of PCI of intermediate coronary stenoses based on FFR were excellent (annual event rate 1.6%/year), FFR is a useful index to judge the indication of PCI and risk-stratify patients for MACE.
Journal of Cardiology 05/2011; 58(1):32-7. · 1.28 Impact Factor
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Akiomi Yoshihisa,
Takashi Owada,
Yasuto Hoshino,
Makiko Miyata,
Tomofumi Misaka,
Takamasa Sato,
Satoshi Suzuki, Nobuo Sakamoto,
Koichi Sugimoto,
Hiroyuki Kunii,
Kazuhiko Nakazato,
Hitoshi Suzuki,
Shu-Ichi Saitoh,
Toshiyuki Ishibashi,
Yasuchika Takeishi
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ABSTRACT: Non-invasive detection of vascular dysfunction in the early stage is clinically important in patients with sleep apnea syndrome (SAS). Flow-mediated dilatation (FMD) is a novel clinical marker of endothelial function. However, it is not clear whether this is useful in the SAS patient.
Echocardiographic parameters and FMD were measured in 129 patients with SAS. Apnea-hypopnea index (AHI) was defined by polygraphy, and patients were divided into the two Groups: Group A (moderate-severe SAS: AHI≥ 15 times/hr, n=93) and Group B (mild SAS: AHI 5-15 times/hr, n=36).
There were no significant differences in echocardiographic parameters between the two groups. However, FMD was significantly lower in Group A than in Group B (3.5±1.6 vs. 7.8±3.1, P< 0.01).
Although cardiac function was not different, vascular dysfunction was evident in patients with moderate-severe SAS. FMD is a useful tool to identify impaired endothelial function non-invasively in patients with SAS.
Fukushima journal of medical science 12/2010; 56(2):115-20.
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ABSTRACT: In the case of acute myocardial infarction (AMI), prompt and appropriate initial treatment is essential for increasing the rate of survival and early reperfusion is a main determinant factor for long-term prognosis. The survival of a patient with refractory ventricular fibrillation was made possible by cooperative emergency medical care including air medical transport, despite long distance to the hospital. The patient was a 60-year-old man. Under a diagnosis of AMI, a helicopter emergency medical service (HEMS) with medical staff on board was requested. Although ventricular fibrillation (VF) occurred at the scene, quick and appropriate advanced cardiovascular life support (ACLS) was provided by the attending doctor, leading to the return of heartbeat. Since the patient still exhibited serious bradycardia and cardiac failure, he was airlifted while undergoing transcutaneous pacing. Upon arrival at the hospital, the patient underwent emergency percutaneous coronary intervention (PCI). During the PCI, VF recurred and chest compressions and a total of 17 defibrillations were performed. The PCI was continued with percutaneous cardiopulmonary support (PCPS). The patient survived without sequelae. Smoother cooperation between pre-hospital medical procedures and post-hospital emergency care is considered to be essential for the survival of patients such as this case.
Fukushima journal of medical science 12/2010; 56(2):139-43.
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Masashi Kamioka,
Toshiyuki Ishibashi,
Hiroshi Ohkawara,
Ryoji Nagai,
Koichi Sugimoto,
Hironori Uekita,
Takanori Matsui,
Sho-Ichi Yamagishi,
Katsuya Ando,
Takayuki Sakamoto, Nobuo Sakamoto,
Yoh Takuwa,
Ikuo Wada,
Masashi Shiomi,
Yukio Maruyama,
Yasuchika Takeishi
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ABSTRACT: An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a key role in diabetic vascular complications. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been shown to function not only as a proteolytic enzyme but also as a signaling molecule. In this study, we investigated the role of MT1-MMP in the AGE/RAGE-triggered signaling pathways in cultured rabbit smooth muscle cells (SMCs) and the molecular interaction between RAGE and MT1-MMP in vitro and in vivo. In SMCs, AGE-activated Rac1 and p47(phox) within 1 min, NADPH oxidase activity and reactive oxygen species (ROS) generation within 5 min, and NF-κB phosphorylation within 15 min, thereby inducing redox-sensitive molecular expression. Silencing of RAGE by small-interfering RNA (siRNA) blocked the AGE-induced signaling pathways. AGE-induced geranylgeranyl transferase I (GGTase I) activity, Rac1·p47(phox) activation, NADPH oxidase activity, ROS generation, and molecular expression were also markedly attenuated by silencing of MT1-MMP. An inhibitor of GGTase I mimicked the effects of MT1-MMP-specific siRNA. Fluorescent immunohistochemistry revealed that MT1-MMP was partially co-localized with RAGE in SMCs, and RAGE was found to form a complex with MT1-MMP in both cultured SMCs and the aortae of diabetic rats by immunoprecipitation. Furthermore, MT1-MMP and RAGE formed a complex in the aortic atherosclerotic lesions of hyperlipidemic rabbits. We show that MT1-MMP plays a crucial role in RAGE-activated NADPH oxidase-dependent signaling pathways and forms a complex with RAGE in the vasculature, thus suggesting that MT1-MMP may be a novel therapeutic target for diabetic vascular complications.
Journal of Cellular Physiology 10/2010; 226(6):1554-63. · 3.87 Impact Factor
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Masashi Kamioka,
Toshiyuki Ishibashi,
Koichi Sugimoto,
Hironori Uekita,
Ryoji Nagai, Nobuo Sakamoto,
Katsuya Ando,
Hiroshi Ohkawara,
Tamio Teramoto,
Yukio Maruyama,
Yasuchika Takeishi
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ABSTRACT: Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis.
We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan.
Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47(phox) membrane translocation, reactive oxygen species (ROS) generation and NF-kappaB phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade.
The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications.
Journal of atherosclerosis and thrombosis 04/2010; 17(6):590-600. · 2.69 Impact Factor
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ABSTRACT: Advanced glycation end products (AGE) play a key role in diabetic vascular complications, whereas matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. This study was conducted to investigate the association of AGE-mediated MMP-9 and apoptosis with the renin-angiotensin system (RAS). We also examined the correlation between plasma HbA1c levels and plaque parameters.
We used autopsy specimens from the aortae and coronary arteries of patients with or without diabetes (n=11, each group) for the immunohistochemistry of AGE, MMP-9, angiotensin-converting enzyme (ACE), and the receptor for AGE (RAGE). Apoptosis was determined by TUNEL staining.
The proportions of AGE accumulation, MMP-9 expression and apoptosis in intimal areas of both aortic and coronary specimens of diabetics were greater than in nondiabetics. MMP-9 expression and apoptosis were correlated with AGE accumulation. RAGE expression was significantly increased in diabetic specimens compared to nondiabetes. Interestingly, the expression of ACE in diabetic specimens was increased and also correlated with AGE accumulation, RAGE expression, MMP-9 expression, and apoptosis in all specimens from diabetics and nondiabetics. Plasma levels of HbA1c were linearly correlated with AGE accumulation, MMP-9, apoptosis, and ACE expression.
The present study shows that AGE/RAGE-related MMP-9 expression and apoptosis were correlated with ACE expression in diabetic plaques and that RAS may be involved in AGE-dependent diabetic vascular complications.
Journal of atherosclerosis and thrombosis 03/2010; 17(6):578-89. · 2.69 Impact Factor
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Nobuo Sakamoto,
Toshiyuki Ishibashi,
Koichi Sugimoto,
Tatsuya Sawamura,
Takayuki Sakamoto,
Nobutaka Inoue,
Shu-ichi Saitoh,
Masashi Kamioka,
Hironori Uekita,
Hiroshi Ohkawara,
Koji Suzuki,
Tamio Teramoto,
Yukio Maruyama,
Yasuchika Takeishi
[show abstract]
[hide abstract]
ABSTRACT: This study was conducted to examine the role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in monocyte adhesion-induced redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in endothelial cells (ECs). LOX-1 was blocked by an antibody-neutralizing LOX-1 TS92 or small interfering RNA. In cultured human aortic ECs, monocyte adhesion activated Rac1 and p47phox, and increased NADPH oxidase activity and reactive oxygen species (ROS) generation within 30 min and NF-κB phosphorylation within 1 h, resulting in redox-sensitive gene expression. Akt and eNOS phosphorylation was induced 15 min after adding monocytes and returned to control level after 30 min, whereas NO production was not altered by monocyte adhesion. Blockade of LOX-1 blunted the monocyte adhesion-triggered redox-sensitive signaling pathway and Akt/eNOS phosphorylation in ECs. Both endothelial intracellular Ca2+ mobilization and Ca2+ influx caused by monocyte attachment were markedly attenuated by pretreatment of ECs with TS92. This suggests that LOX-1 is involved in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of oxidized low-density lipoprotein (ox-LDL). Furthermore, blockade of Ca2+ inhibited monocyte adhesion-triggered Rac1 and p47phox activation and ROS generation in ECs, whereas Ca2+ signaling was suppressed by blockade of NADPH oxidase and ROS generation. Finally, TS92 blocked the monocyte adhesion to ECs stimulated with or without tumor necrosis factor- or ox-LDL. We provide evidence that LOX-1 plays a role in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of the ox-LDL–LOX-1 axis. J. Cell. Physiol. 220: 706–715, 2009. © 2009 Wiley-Liss, Inc.
Journal of Cellular Physiology 08/2009; 220(3):706 - 715. · 3.87 Impact Factor
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Koichi Sugimoto,
Toshiyuki Ishibashi,
Tatsuya Sawamura,
Nobutaka Inoue,
Masashi Kamioka,
Hironori Uekita,
Hiroshi Ohkawara,
Takayuki Sakamoto, Nobuo Sakamoto,
Yasuo Okamoto,
Yoh Takuwa,
Akemi Kakino,
Yoshiko Fujita,
Takeshi Tanaka,
Tamio Teramoto,
Yukio Maruyama,
Yasuchika Takeishi
[show abstract]
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ABSTRACT: RhoA and Rac1 activation plays a key role in endothelial dysfunction. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells (ECs). Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be involved in atherogenesis. This study was conducted to investigate the role of the LOX-1-MT1-MMP axis in RhoA and Rac1 activation in response to ox-LDL in ECs.
Ox-LDL induced rapid RhoA and Rac1 activation as well as MT1-MMP activity in cultured human aortic ECs. Inhibition of LOX-1 prevented ox-LDL-dependent RhoA and Rac1 activation. Knockdown of MT1-MMP by small interfering RNA prevented ox-LDL-induced RhoA and Rac1 activation, indicating that MT1-MMP is upstream of RhoA and Rac1. Fluorescent immunostaining revealed the colocalization of LOX-1 and MT1-MMP, and the formation of a complex of LOX-1 with MT1-MMP was detected by immunoprecipitation. Blockade of LOX-1 or MT1-MMP prevented RhoA-dependent endothelial NO synthase protein downregulation and cell invasion, Rac1-mediated NADPH oxidase activity, and reactive oxygen species generation.
The present study provides evidence that the LOX-1-MT1-MMP axis plays a crucial role in RhoA and Rac1 activation signalling pathways in ox-LDL stimulation, suggesting that this axis may be a promising target for treating endothelial dysfunction.
Cardiovascular research 07/2009; 84(1):127-36. · 5.80 Impact Factor
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Nobuo Sakamoto,
Toshiyuki Ishibashi,
Koichi Sugimoto,
Tatsuya Sawamura,
Takayuki Sakamoto,
Nobutaka Inoue,
Shu-Ichi Saitoh,
Masashi Kamioka,
Hironori Uekita,
Hiroshi Ohkawara,
Koji Suzuki,
Tamio Teramoto,
Yukio Maruyama,
Yasuchika Takeishi
[show abstract]
[hide abstract]
ABSTRACT: This study was conducted to examine the role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in monocyte adhesion-induced redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in endothelial cells (ECs). LOX-1 was blocked by an antibody-neutralizing LOX-1 TS92 or small interfering RNA. In cultured human aortic ECs, monocyte adhesion activated Rac1 and p47(phox), and increased NADPH oxidase activity and reactive oxygen species (ROS) generation within 30 min and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive gene expression. Akt and eNOS phosphorylation was induced 15 min after adding monocytes and returned to control level after 30 min, whereas NO production was not altered by monocyte adhesion. Blockade of LOX-1 blunted the monocyte adhesion-triggered redox-sensitive signaling pathway and Akt/eNOS phosphorylation in ECs. Both endothelial intracellular Ca2+ mobilization and Ca2+ influx caused by monocyte attachment were markedly attenuated by pretreatment of ECs with TS92. This suggests that LOX-1 is involved in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of oxidized low-density lipoprotein (ox-LDL). Furthermore, blockade of Ca2+ inhibited monocyte adhesion-triggered Rac1 and p47(phox) activation and ROS generation in ECs, whereas Ca2+ signaling was suppressed by blockade of NADPH oxidase and ROS generation. Finally, TS92 blocked the monocyte adhesion to ECs stimulated with or without tumor necrosis factor-alpha or ox-LDL. We provide evidence that LOX-1 plays a role in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of the ox-LDL-LOX-1 axis.
Journal of Cellular Physiology 06/2009; 220(3):706-15. · 3.87 Impact Factor
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Takayuki Sakamoto,
Toshiyuki Ishibashi,
Koichi Sugimoto, Nobuo Sakamoto,
Hiroshi Ohkawara,
Miki Niinuma,
Kenji Nagata,
Masashi Kamioka,
Naotoshi Sugimoto,
Atai Watanabe,
Masahiko Kurabayashi,
Yoh Takuwa,
Yukio Maruyama
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ABSTRACT: We investigated the role of RhoA activation and its mechanism in plasminogen activator inhibitor-1 (PAI-1) gene expression induced in endothelial cells by monocyte adhesion. Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased PAI-1 expression at the transcriptional level and activated RhoA which was accompanied by an increase in the activity of geranylgeranyl transferase I (GGTase I), an enzyme responsible for geranylgeranylation, and actin stress fiber formation. Inhibition of RhoA by C3 exoenzyme or by adenovirus-mediated expression of N19RhoA, as well as by pravastatin, prevented the upregulation of PAI-1 induced by monocyte adhesion. GGTI-286, an inhibitor of GGTase I, prevented the monocyte-induced RhoA activation and PAI-1 expression in endothelial cells. Monocyte attachment induced an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in endothelial cells and Ca(2+) chelation prevented the increased promoter activity and expression of PAI-1 induced by monocyte adhesion. C3 exoenzyme and GGTI-286 also suppressed endothelial intracellular Ca(2+) mobilization and Ca(2+) entry induced by monocytes. The present study shows that GGTase I plays a role in the RhoA activation in endothelial cells induced by monocyte adhesion and that GGTase I-mediated Ca(2+) signaling may contribute to RhoA-dependent PAI-1 gene expression.
Atherosclerosis 08/2007; 193(1):44-54. · 3.79 Impact Factor
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Takayuki Sakamoto,
Toshiyuki Ishibashi, Nobuo Sakamoto,
Koichi Sugimoto,
Kensuke Egashira,
Hiroshi Ohkawara,
Kenji Nagata,
Keiko Yokoyama,
Masashi Kamioka,
Toshihiro Ichiki,
Naotoshi Sugimoto,
Masahiko Kurabayashi,
Koji Suzuki,
Yoh Takuwa,
Yukio Maruyama
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[hide abstract]
ABSTRACT: Ca2+ plays an important role in tissue factor (TF) gene expression. We investigated the role of endogenous nitric oxide (NO) in the induction of TF expression in endothelial cells (ECs) by monocyte adhesion and the mechanisms of NO action.
Inhibition of endogenous NO by Nomega-nitro-L-arginine methyl ester (L-NAME) enhanced TF promoter activity and protein expression induced in human coronary ECs by monocyte adhesion, as well as EC surface TF activity. L-NAME also induced monocyte chemoattractant protein-1 (MCP-1) expression, which was blocked by an NO donor, NOC18. Exogenous MCP-1 enhanced TF expression induced by monocyte adhesion, whereas adenovirus-mediated expression of the mutant MCP-1, 7ND, abolished the L-NAME enhancement of TF expression induced by monocyte adhesion. Monocyte attachment to L-NAME-treated ECs increased Ca2+ influx, which was prevented by NOC18, anti-MCP-1 antibody or 7ND. These results indicate that the binding of increased MCP-1 induced by endogenous NO blockade to CCR2 mediated the enhancement of Ca2+ influx only when monocytes adhered to ECs, which upregulated TF expression in ECs triggered by monocyte adhesion.
MCP-1/CCR2 may play a role in Ca2+ influx-dependent TF regulation in the monocyte-EC interaction in the impairment of NO synthesis.
Arteriosclerosis Thrombosis and Vascular Biology 10/2005; 25(9):2005-11. · 6.37 Impact Factor
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Hiroshi Ohkawara,
Toshiyuki Ishibashi,
Takayuki Sakamoto,
Koichi Sugimoto,
Kenji Nagata,
Keiko Yokoyama, Nobuo Sakamoto,
Masashi Kamioka,
Isao Matsuoka,
Shigetomo Fukuhara,
Naotoshi Sugimoto,
Yoh Takuwa,
Yukio Maruyama
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ABSTRACT: RhoA plays a critical signaling role in thrombin-induced endothelial dysfunction. The possible thrombin regulation of geranylgeranylation, a lipid modification, of unprocessed RhoA and the significance of the geranylgeranylation in RhoA activation in endothelial cells (ECs) are not well understood. The amounts of the unprocessed and geranylgeranylated forms of RhoA in non-stimulated cultured human aortic ECs were 31 +/- 8 and 69 +/- 8% total cellular RhoA, respectively (n = 6, p < 0.0001), as determined by the Triton X-114 partition method. Thrombin-induced rapid conversion of most of the unprocessed RhoA into the geranylgeranylated form within 1 min through stimulating geranylgeranyltransferase I (GGTase I) activity. Thrombin-induced rapid geranylgeranylation was inhibited by acute short term (3 min) pretreatment with atorvastatin as well as by an inhibitor of GGTase I (GGTI-286). Thrombin also rapidly stimulated GTP loading of RhoA, which was blocked by acute pretreatment with either atorvastatin or GGTI-286. These observations indicate the dependence of thrombin stimulation of RhoA on the rapid geranylgeranylation of unprocessed RhoA. Importantly, the addition of geranylgeranylpyrophosphate to ECs pretreated with atorvastatin quickly reversed the atorvastatin inhibition of thrombin stimulation of RhoA. These results suggest that geranylgeranylation of unprocessed RhoA may limit thrombin-induced full activation of RhoA in ECs. Cytoskeleton analysis demonstrated that atorvastatin and GGTI-286 inhibited thrombin-induced stress fiber formation. We provide the evidence that, in thrombin-stimulated ECs, the unprocessed form of RhoA is rapidly geranylgeranylated to become the mature form, which then is converted into GTP-bound active RhoA.
Journal of Biological Chemistry 03/2005; 280(11):10182-8. · 4.77 Impact Factor
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ABSTRACT: There is a syndrome consisting of acute infarction-like symptoms and ECG findings, and transient left ventricular apical ballooning without epicardial coronary artery obstruction. A 67-year-old female admitted to our hospital because of severe anterior chest pain was diagnosed as having this syndrome. Since stenotic, spastic, or occlusive sites were not found in epicardial coronary arteries by emergency cardiac catheterization, we speculated coronary microvasculature involvement in the pathophysiology of the event. Four weeks later in a drug-free condition, there was no significant epicardial coronary vasospasm by intracoronary acetylcholine administration (IC-ACh). The average peak flow velocity (APFV) of the left coronary artery (LCA) was measured using the Doppler flow wire method. Under maximal dilatation of the epicardial LCA by intracoronary nitroglycerin administration, IC-ACh was again performed taking into consideration that the change in APFV in response to IC-ACh reflects a coronary microvascular response to it. In the nonischemic control subjects, basal APFV increased to 296+/-29% (n = 24) of the basal value after IC-ACh. In this patient, although IC-ACh did not cause vasospasm in epicardial LCA, APFV was decreased to 54% of its basal value. After administration of a Ca antagonist and KATP opener, she had no chest symptoms and was discharged from the hospital. In 2003, she forgot to take her medication for 3 days and then experienced a sudden recurrence of the same type of attack. She started her medication again and her symptoms disappeared. Three weeks later, she underwent an assessment of the coronary microvascular response to ACh with medicine. Her APFV after ACh increased to 177% of the basal value.
International Heart Journal 02/2005; 46(1):147-52. · 1.16 Impact Factor
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Toshiyuki Ishibashi,
Takayuki Sakamoto,
Hiroshi Ohkawara,
Kenji Nagata,
Koichi Sugimoto,
Sotaro Sakurada,
Naotoshi Sugimoto,
Atai Watanabe,
Keiko Yokoyama, Nobuo Sakamoto,
Masahiko Kurabayashi,
Yoh Takuwa,
Yukio Maruyama
[show abstract]
[hide abstract]
ABSTRACT: The role of Rho activation in the regulation of tissue factor (TF) is not clear. This study was undertaken to investigate this in endothelial cells induced by monocyte adhesion.
Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased the levels of TF antigen in the endothelial cells. The results of transient transfection of the human TF promoter/luciferase gene into endothelial cells indicated that the increase in endothelial expression of the TF gene caused by monocyte adhesion occurred at the transcriptional level. The upregulation of TF was inhibited by statins, and the suppressive effect of statins was reversed by geranylgeranylpyrophosphate. Monocyte adhesion rapidly upregulated the membrane translocation and GTP/GDP exchange of RhoA, but not of Cdc42 or Rac, in endothelial cells. Rho inhibition by C3 exoenzyme or adenovirus-mediated expression of N19RhoA prevented the endothelial upregulation of TF caused by monocyte adhesion, and this was mimicked by Rho-kinase inhibitors. Moreover, monocyte adhesion increased the phosphorylation of nuclear factor-kappaB p65 in endothelial cells, and this was prevented by statins and Rho inhibition.
Our study shows that RhoA activation plays an integral role in TF expression in endothelial cells.
Arteriosclerosis Thrombosis and Vascular Biology 05/2003; 23(4):681-7. · 6.37 Impact Factor
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Yukihiko Abe,
Tukasa Asakura, Nobuo Sakamoto,
Shunichi Ishikawa,
Syuichi Muroi,
Fujiko Saitoh,
Masahiko Satoh,
Shigebumi Suzuki,
Masahiro Ono,
Atsushi Sakabe,
Masumi Iwai,
Masahito Sando,
Jun Gotou,
Yasuyuki Watanabe,
Kenji Nagata,
Kazuhira Maehara,
Yukio Maruyama
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ABSTRACT: It is very important to prevent embolisms from left atrial thrombi (LAT). The present study was a trial for the management of patients with AT using 122 patients with atrial fibrillation and LAT who were followed for 1 year after transesophageal echocardiography. LAT were classified by their shape and mobility into the mobile ball type (MB, n=28), fixed ball type (FB, n=32) and mountain type (MO, n=42). The patients were given warfarin (INR: 1.5-2.0, n=43), aspirin 81 mg (n=74) and/or ticlopidine 200 mg/day (n=31). The embolic rate (ER) in the MB group was significantly higher than in the other groups [ie, MB 39.3% vs FB 15.6% (p<0.05), vs MO 2.4% (p<0.05)]. The ER in the FB group was significantly higher than in the MO group (p<0.05). Therapy with a combination of ticlopidine and aspirin reduced the ER in the patients with ball thrombi. The ER of the ball thrombus type group, especially the MB group, was very high in spite of therapy with anti-coagulants and/or anti-platelet agents, and such patients should be treated by early surgical intervention. However, the combination of ticlopidine and aspirin may be useful for preventing embolism.
Circulation Journal 03/2003; 67(3):203-8. · 3.77 Impact Factor
