基本情報
研究キーワード
4研究分野
1委員歴
5-
2012年 - 2014年
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2014年
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2014年
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2014年
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2012年
受賞
7-
2010年3月
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2009年5月
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2006年11月
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2002年7月
論文
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IJC Heart & Vasculature 54 101507-101507 2024年10月
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Hypertension research : official journal of the Japanese Society of Hypertension 2024年9月19日The Japanese Society of Hypertension have established a blood pressure (BP) target of 130/80 mmHg for patients with coronary artery disease (CAD). We evaluated the data of 8793 CAD patients in the Clinical Deep Data Accumulation System database who underwent cardiac catheterization at six university hospitals and the National Cerebral and Cardiovascular Center (average age 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). Patients were divided into two groups based on whether or not they achieved the guideline-recommended BP of <130/80 mmHg. We analyzed the relationship between BP classification and major adverse cardiac and cerebral event (MACCE) separately in two groups: those with ACS and those with chronic coronary syndrome (CCS). During an average follow-up period of 33 months, 710 MACCEs occurred. A BP below 130/80 mmHg was associated with fewer MACCEs in both the overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-1.00, p = 0.048) and the ACS group (HR 0.67, 95%CI 0.51-0.88, p = 0.003). In particular, stroke events were also lower among those with a BP below 130/80 mmHg in both the overall (HR 0.69, 95%CI 0.53-0.90, p = 0.006) and ACS groups (HR 0.44, 95%CI 0.30-0.67, p < 0.001). In conclusion, the achievement of BP guidelines was associated with improved outcomes in CAD patients, particularly in reducing stroke risk among those with ACS.
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International Journal of Cardiology: Cardiovascular Risk and Prevention 22 2024年9月The authors regret that the original version of the article incorrectly stated the study period as “April 2014 to March 2020" in both the Abstract and the Methods section. The correct study period should have been “April 2013 to March 2019". The authors would like to apologise for any inconvenience caused.
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JACC: Advances 3(7) 2024年7月Background: The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. Objectives: This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. Methods: The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. Results: Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. Conclusions: The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730)
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JACC. Advances 3(7) 100996-100996 2024年7月BACKGROUND: The prognostic implications of persistent low-grade inflammation in patients with chronic coronary syndrome (CCS) are underexplored. The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) study demonstrated the benefit of higher intensity pitavastatin in Japanese patients with CCS. OBJECTIVES: This prespecified subanalysis of the REAL-CAD study aimed to assess the prognostic effect of the persistent low-grade inflammation represented by high-sensitivity C-reactive protein (hs-CRP) in CCS patients. METHODS: The present analysis involved patients without events until 6 months after randomization and whose hs-CRP levels were available at baseline and 6 months (n = 10,460). The primary endpoint was the composite of cardiovascular mortality, myocardial infarction, stroke, and unstable angina hospitalization. Landmark analyses evaluated the prognostic impact of continuous inflammation in 4 groups based on the median levels of hs-CRP (0.5 mg/L for both) at baseline and 6 months. The 4 groups included patient with persistently low, elevated (increased), reduced, and persistently high hs-CRP. RESULTS: Adjusted Cox proportional hazard analyses demonstrated an increased risk of the primary endpoint in the group with persistently high hs-CRP when compared to the group with persistently low hs-CRP as a reference (adjusted HR: 1.48, 95% CI: 1.18-1.89; P = 0.001), but with a similar risk in the group with elevated (HR: 1.07, 95% CI: 0.77-1.49, P = 0.68) and reduced (HR: 0.92; 95% CI: 0.66-1.27; P = 0.60) hs-CRP. CONCLUSIONS: The study shows that persistent low-grade inflammation is associated with poor outcomes and underscores the need to address residual inflammatory risk in CCS patients. (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease [REAL-CAD]; NCT01042730).
MISC
1913-
Japanese circulation journal 65 613-613 2001年4月20日
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Therapeutic Research 22(4) 805-805 2001年4月発作性心房細動の薬物治療において,Ic群薬が心房粗動を惹起しやすいという観察は得られなかった
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NATURE MEDICINE 7(4) 382-383 2001年4月
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JOURNAL OF BIOLOGICAL CHEMISTRY 276(16) 12624-12628 2001年4月The asialoglycoprotein receptor is an abundant hetero-oligomeric endocytic receptor that is predominantly expressed on the sinusoidal surface of the hepatocytes, A number of physiological and pathophysiological functions have been ascribed to this hepatic lectin (HL), the removal of desialylated serum glycoproteins and apoptotic cells, clearance of lipoproteins, and the sites of entry for hepatotropic viruses. The assembly of two homologous subunits, HL-1 and HL-2, is required to form functional, high affinity receptors on the cell surface. However, the importance of the individual subunits for receptor transport to the cell surface is controversial. We have previously generated HL-S-deficient mice and showed that the expression of HL-1 was significantly reduced, and the functional activity as the asialoglycoprotein receptor was virtually eliminated. However, we failed to detect phenotypic abnormalities. To explore the significance of the major HL-1 subunit for receptor expression and function in vivo, we have disrupted the HL-1 gene in mice. Homozygous HL-1-deficient animals are superficially normal. HL-2 expression in the liver is virtually abrogated, indicating that HL-1 is strictly required for the stable expression of HL-2, Although these mice are almost unable to clear asialo-orosomucoid, a high affinity ligand for asialoglycoprotein receptor, they do not accumulate desialylated glycoproteins or lipoproteins in the plasma.
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Molecular and cellular biology 21(7) 2521-32 2001年4月 査読有りTo investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1(-/-)), IRS-2 deficient (IRS-2(-/-)), and IRS-1 IRS-2 double deficient (IRS-1(-/-) IRS-2(-/-)), from mouse embryos of the corresponding genotypes. The abilities of IRS-1(-/-) cells and IRS-2(-/-) cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1(-/-) IRS-2(-/-) cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) is severely decreased in IRS-1(-/-) IRS-2(-/-) cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1(-/-) IRS-2(-/-) cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1(-/-) IRS-2(-/-) cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPalpha and PPARgamma, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1(-/-) IRS-2(-/-) double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPalpha and PPARgamma expression and adipocyte differentiation.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 281(4) 1057-1062 2001年3月Hypoxia-inducible factor 1 (HIF-1) is composed of HIF-1 alpha and arylhydocarbon nuclear receptor translocator (ARNT), which belong to the basic-helix-loop-helix-Per/ARNT/Sim bHLH-PAS) family of transcription factors. HLF plays key roles in oxygen homeostasis and embryonic cardiovascular development. In this study, we have cloned cDNAs encoding the chick HIF-1 alpha from cultured embryonic ventricular myocytes (CEVM) and then examined its expression in various embryonic tissues. The deduced amino acid sequence of the chick HIF-1 alpha cDNA showed 79% identity with that of the human HIF-1 alpha cDNA. In contrast, sequence homology between the chick HIF-1 alpha and endothelial PAS protein 1 (EPAS1), another member of the bHLH-PAS proteins, was only low (49%). HIF-1 alpha mRNA was expressed abundantly in CEVM., but scarcely in the liver, which was quite different from expression pattern of EPAS1 mRNA. These data suggest that HIF-1 alpha may be involved in embryonic cardiovascular development. HIF-1 alpha and EPAS1 may play distinct roles during developmental stages. (C) 2001 Academic Press.
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ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 21(3) 372-377 2001年3月Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus, Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 <mu>m(2) vs 351 738+/-175 597 mum(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density Lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.
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PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY 24(3) 381-383 2001年3月Screw-in atrial pacing leads are widely used. Cardiac tamponade is a complication. An 82-year-old woman with advanced atrioventricular block underwent permanent pacemaker implantation and subsequently developed cardiac tamponade. At surgery, the lead-tip screw was found penetrated through the right atrium but nor through the pericardium. The source of bleeding was confirmed to scratching the inner pericardial membrane by the screw tip. Although cardiac tamponade due to perforation and leakage is known, tamponade caused by the trauma of an atrial screw on the pericardium with resultant ooze is less well described.
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Pacing and clinical electrophysiology : PACE 24(3) 381-3 2001年3月 査読有りScrew-in atrial pacing leads are widely used. Cardiac tamponade is a complication. An 81-year-old woman with advanced atrioventricular block underwent permanent pacemaker implantation and subsequently developed cardiac tamponade. At surgery, the lead-tip screw was found penetrated through the right atrium but not through the pericardium. The source of bleeding was confirmed to scratching the inner pericardial membrane by the screw tip. Although cardiac tamponade due to perforation and leakage is known, tamponade caused by the trauma of an atrial screw on the pericardium with resultant ooze is less well described.
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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 37(2) 248A-248A 2001年2月
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The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20(2) 228-228 2001年2月 査読有り
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THROMBOSIS AND HAEMOSTASIS 85(2) 226-230 2001年2月The platelet-collagen receptor, glycoprotein Ia/IIa (integrin alpha (2)beta (1)) plays a fundamental role in the adhesion of platelets to fibrillar collagen, an event leading to platelet activation and thrombus formation and contributing to the pathogenesis of thrombotic disease. Further, glyco protein Ia/IIa receptor density and function may be associated with two linked and silent polymorphisms (C-807/T and (873)G/A) within the glycoprotein Ia gene. We tested the extent to which these polymorphisms serve as genetic markers of myocardial infarction in a Japanese population. A case-control study was carried out using 210 Japanese myocardial infarction patients and 420 age- and sex-matched controls. Genotyping was accomplished using PCR followed by melting curve analysis with specific fluorescent hybridization probes. The (CC)-C-807. CT, TT genotypes linked perfectly to the (873)GG, GA, AA genotypes, respectively. Allele frequencies of the T-807 ((873)A) variant were similar in the control and patient groups (0.373 vs. 0.352). The T-807 and (873)A variants of platelet glycoprotein la gene are common and in a perfect linkage in the Japanese population, but it appears unlikely that the T-807 ((873)A) variant represents a useful marker of increased risk for myocardial infarction.
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KIDNEY INTERNATIONAL 59(2) 645-653 2001年2月Background. We have recently found that chronic infusion of angiotensin II (Ang II) into rats resulted in an impairment of renal function, whereas norepinephrine (NE) infusion did not. We investigated whether chronic infusion of Ang II and NE caused different degrees of renal cell apoptosis and proliferation. Methods. Rats were made hypertensive via continuous infusion of either Ang II or NE for up to seven days. Renal cell apoptosis and proliferation were analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique and staining with antibody against proliferating cell nuclear antigen (PCNA), respectively. In some experiments, an inducer or inhibitor of heme oxygenase-l (HO-1) was administered to investigate the possible role of HO-1 in renal cell homeostasis. Results. Infusion of Ang II. but not NE, resulted in approximately a sevenfold increase in bax protein at seven days of infusion. The TUNEL assay revealed that Ang II infusion significantly increased the number of apoptotic cells, whereas NE infusion did not. TUNEL- and PCNA-positive cells were mainly seen in the tubulointerstitial region of Ang II-infused rats. Ang II induced increased positivity of TUNEL, and PCNA was blocked completely by losartan, but only partially by hydralazine. Induction of HO-1 reduced and inhibition of HO increased Ang II-induced cell proliferation. Conclusions. These data suggest that Ang II plays a pivotal role in the development of renal cell proliferation and apoptosis in the setting of hypertension. The renal HO system may modulate proliferative and pro-apoptotic effects of Ang II.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 280(4) 1183-1188 2001年2月Galectin-3, a member of beta -galactoside-binding lectin family, is suggested to be an AGE-receptor. To examine this possibility, we prepared CHO cells overexpressing human galectin-3 (galectin-3-CHO cells). Galectin-3-CHO cells showed a specific and saturable binding to I-125-AGE-BSA with Kd of 3.1 mug/ml. I-125-AGE-BSA was endocytosed by galectin-3-CHO cells and underwent lysosomal degradation. The endocytosis of I-125-AGE-BSA was inhibited not only by unlabeled AGE-BSA but also by acetylated LDL and oxidized LDL, ligands for the scavenger receptor family. Furthermore, I-125-oxidized LDL and I-125-acetylated LDE were actively endocytosed by galectin-3-CHO cells and the incubation with acetyl-LDL led to intracellular accumulation of cholesteryl esters, indicating the role of galectin-3 in endocytosis of AGE-proteins and modified LDLs. Since galectin-3 was localized and upregulated in foam cells at human atherosclerotic lesions, the present results suggest that galectin-3 plays an important role in formation of atherosclerotic lesions in vivo, by modulating endocytic uptake of AGE-proteins and modified LDLs. (C) 2001 Academic Press.
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Gastroenterology 120(2) 460-9 2001年2月 査読有りBACKGROUND & AIMS: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. METHODS: PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed. RESULTS: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway. CONCLUSIONS: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
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Circulation research 88(1) 52-8 2001年1月19日 査読有りRecent studies have shown that the homeobox gene Hex plays an important role in inducing differentiation of vascular endothelial cells. In this study, we examined the expression of Hex in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Immunohistochemistry showed a marked induction of Hex protein in neointimal VSMCs after balloon injury in rat aorta. Western and reverse transcriptase-polymerase chain reaction analyses demonstrated that Hex was abundantly expressed in cultured VSMCs, whereas it was undetectable in other cell types or in normal aorta. The expression pattern of Hex was similar to that of SMemb/NMHC-B, a nonmuscle isoform of myosin heavy chain that we have previously reported to be a molecular marker of dedifferentiated VSMCs. We next examined the role of Hex in SMemb gene transcription. Promoter analysis demonstrated that the sequence identical to consensus cAMP-responsive element (CRE) located at -481 of the SMemb promoter was critical for Hex responsiveness. Mutant Hex expression vector, which lacks the homeodomain, failed to stimulate SMemb gene transcription, suggesting the requirement of the homeodomain for its transactivation. Elecrophoretic mobility shift assay showed that Hex binds to a consensus binding sequence for homeobox proteins, but not to CRE. Cotransfection of protein kinase A expression vector increased the ability of Hex to stimulate SMemb promoter activity in a CRE-dependent manner. Overexpression of CRE binding protein (CREB), but not Mut-CREB which contains mutation at Ser133, strongly activated Hex-induced SMemb promoter activity. These results suggest that Hex mediates transcriptional induction of the SMemb/NMHC-B gene via its homeodomain, and Hex can function as a transcriptional modulator of CRE-dependent transcription in VSMCs.
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Circulation 103(1) 133-9 2001年1月2日 査読有りBACKGROUND: Increasing evidence indicates that elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and endothelial dysfunction, although little specific information on the mechanisms responsible for the atherogenic effects of homocysteine or on the in vivo contribution made by hyperhomocysteinemia to atherosclerosis is currently available. Because homocysteine is known to exert a direct inhibitory effect on endothelial cell growth in vitro, we hypothesized that this effect contributes to the progression of atherosclerotic lesions initiated by endothelial damage caused by mechanical injury. METHODS AND RESULTS: We prepared diet-induced hyperhomocysteinemic rats in which neointima formation after balloon injury to the common carotid artery was assessed. Moderate hyperhomocysteinemia (plasma homocysteine levels 3- to 4-fold higher than control) significantly exacerbated neointima formation. Oral administration of folate, which had a homocysteine-lowering effect, diminished neointima formation induced by moderate hyperhomocysteinemia. Furthermore, the attenuation of reendothelialization was shown in diet-induced hyperhomocysteinemic rats with Evans blue staining. CONCLUSIONS: Diet-induced hyperhomocysteinemia, even mild to moderate, exacerbates neointima formation after denuding injury, making hyperhomocysteinemia a likely risk factor for postangioplasty restenosis. It may be mediated through an inhibitory effect of homocysteine on reendothelialization. Homocysteine lowering with folate supplementation can effectively ameliorate the detrimental effects of moderate hyperhomocysteinemia. Clinical trials would seem to be warranted.
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Journal of Human Genetics 46(9) 549-552 2001年We provide here 29 genetic variations, including 28 novel ones, in five genes that are potentially involved in the excitement of cardiomyocytes: we found 4 in KCNA10, 2 in KCNK1, 8 in KCNK6, 11 in SLC18A1 (VMAT1), and 4 in SLC6A2 (norepinephrine transporter). We also examined their allelic frequencies in a Japanese population of long QT syndrome-affected and nonaffected individuals. These data would be useful for genetic association studies designed to investigate acquired arrhythmias.
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ATHEROSCLEROSIS VI 947 398-402 2001年We recently isolated a novel bHLH/PAS protein, CLIF (cycle like factor), by yeast two-hybrid screening of human umbilical endothelial cell cDNA library. CLIF is preferentially expressed in endothelial and neuronal cells. Because CLIF is expressed in vascular endothelial cells and forms a heterodimer with CLOCK, the key transcription factor controlling the circadian rhythm, we hypothesized that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. Northern blot analysis of mouse organs showed circadian oscillations of PAI-1 mRNA levels. In addition, the clock-related genes also showed circadian oscillation in peripheral tissues. In endothelial cells, the heterodimer of CLIF and CLOCK upregulated the PAI-1 gene expression through E-box sites. Furthermore, Period and Cryptochrome, which are negative regulators in the feedback loop of the biological clock, inhibited PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that the peripheral tissues have their own biological clock and CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. This study suggests a novel molecular mechanism of the morning onset of myocardial infarction. Here we review our recent work and literature.
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ATHEROSCLEROSIS VI 947 26-34 2001年Adrenomedullin (AM) has been implicated as having hypotensive as well as protective effects on organs and vessels against different kinds of injuries. To elucidate the in vivo pathophysiological roles of adrenomedullin, we established transgenic mice (AMTg) overexpressing adrenomedullin driven by preproendothelin-1 promoter and adrenomedullin knockout mice (AMKO). Blood pressure in AMTg was significantly lower than that in wild-type mice, and AMTg was significantly resistant to lipopolysaccharide-induced septic shock and vascular injuries. On the other hand, heterozygotes of AMKO, AM(+/-), were fully viable and hypertensive as compared with wild littermates. Mice homozygous for adrenomedullin null mutation (AM-/-) were embryonic lethal, and no embryos could survive beyond the midterm of gestation. Collectively, our findings Indicate the indispensable role of adrenomedullin in circulatory homeostasis and the organ protection as well as the fetal morphogenesis and the maintenance of pregnancy.
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MOLECULAR AND CELLULAR BIOCHEMISTRY 226(1-2) 57-65 2001年In order to elucidate roles of Ets family of transcription factors in transcriptional activation of inducible nitric oxide synthase (iNOS) genes, we analyzed the chick iNOS gene expression in cultured chick embryonic ventricular myocytes (CEVM). Deletional analysis and site-directed mutagenesis demonstrated that both the Ets/PEA3 site (-221 to -216 bp) and the kappaB site (-101 to -93 bp) of the 5'-flanking region of the chick iNOS gene were involved in the maximal activation of the lipopolysaccharide (LPS)-induced expression of the reporter (luciferase) gene, although the proximal kappaB site played the more essential role. Electrophoretic mobility shift assay revealed that LPS augmented the nuclear protein bindings to the Ets/PEA3 as well as kappaB motifs. Ets-1, one of the Ets proteins, was suggested to be bound to the Ets/PEA3 oligonucleotide. By Northern blot analysis, LPS was shown to induce iNOS mRNA in CEVM, along with a preceding increase in the levels of c-ets-1 mRNA. Ets-1 may be involved in the iNOS gene transcription in CEVM, presumably through interacting with the NF-kappaB.
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European Respiratory Journal 17(2) 316-320 2001年Primary pulmonary hypertension (PPH) is associated with specific structural alterations, including cellular intimal thickening, intimal fibrosis, and plexiform lesions. To determine the phenotypes of smooth muscle cells (SMCs) in such lesions, the authors conducted an immunohistochemical analysis of lung tissues from two patients with PPH, using two antimuscle actin antibodies, HHF35 and CGA7, and two anti-SMC myosin heavy chain markers, anti-SM1 and anti-SM2 antibodies and related antibodies. Cells that stained positive (+) with HHF35, CGA7, anti-SM1, and anti-SM2 were considered to be SMCs of a mature state. Conversely, those that stained positive with HHF35 and anti-SM1, but weakly positive (+/-) or negative (-) with CGA7 and anti-SM2, were considered to be SMCs exhibiting an immature state. Cellular intimal thickening was composed of SMCs of an immature phenotype (HHF35+, CGA7+/-, SM1+, SM2+/-), accompanied by the expression of fibronectin and the presence of macrophages intimal fibrosis contained mature SMCs (HHF35+, CGA7+, SM1+, SM2+) and plexiform lesion consisted of proliferative endothelial cells (von Willebrand factor-positive cells, proliferating cell nuclear antigen-positive cells) and underlying immature SMCs (HHF35+, CGA7-, SM1+, SM2-) associated with fibronectin expression and macrophage infiltration. These findings suggest that smooth muscle cells with specific phenotypes may contribute to the development of specific vascular lesions in primary pulmonary hypertension.
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JOURNAL OF HUMAN GENETICS 46(3) 158-162 2001年We report here 20 single-nucleotide polymorphisms (SNPs), including 15 novel ones, in six genes that are considered to be candidates for long QT syndrome (LQTS): 2 SNPs in KCNB1, 3 in KCND3, 3 in KCNJ11, 7 in ABCC9, 3 in ADRB1, and 2 in SLC18A2. We also examined their allelic frequencies in a Japanese sample population of LQTS-affected and nonaffected individuals. These data will be useful for genetic association studies designed to investigate acquired arrhythmias.
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JOURNAL OF HUMAN GENETICS 46(1) 38-40 2001年Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta -Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta -adrenergic blocking agents than these with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.
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Respirology 6(1) 57-60 2001年Indomethacin is one of the most popular non-steroidal anti-inflammatory drugs (NSAID). Although NSAID occasionally provoke bronchospasm and hypersensitivity pneumonia, they seldom cause lymphadenopathy. This is the first report in which NSAID induced both eosinophilic pneumonia and bulky intrathoracic lymphadenopathy simultaneously. A 76-year-old Japanese man experienced high fever and dyspnoea after using an indomethacin suppository. Computed tomography scan of his chest revealed massive mediastinal and hilar lymphadenopathy along with diffuse infiltration in both lungs. He was diagnosed to have eosinophilic pneumonia because of eosinophilia in his peripheral blood and bronchoalveolar lavage fluid (BALF). Without using glucocorticoids, the pulmonary infiltration and lymphadenopathy subsided spontaneously. As the blastoid transformation test using the lymphocytes in his BALF was positive to indomethacin, we judged that both his eosinophilic pneumonia and mediastinal lymphadenopathy were due to a hypersensitivity reaction to indomethacin. An allergic reaction to NSAID should be considered as a rare cause of mediastinal lymphadenopathy.
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine 42(1) 130-7 2001年1月 査読有りUNLABELLED: Aortic dissection is among the most common of fatal conditions of the aorta. Prompt and accurate diagnosis of the site and extent of the lesion is necessary for adequate therapy. However, this catastrophic disease, characterized by extensive damage to smooth muscle cells, lacks specific signs and symptoms. As a result, the diagnosis is still frequently missed today and a new diagnostic method to specifically identify aortic dissection would be attractive. The purpose of this study was to examine the feasibility of radioimmunoscintigraphy using 99mTc-anti-smooth muscle myosin monoclonal antibody (SM-MAb) for the noninvasive diagnosis of aortic dissection in the rat experimental model. METHODS: The accumulation of 99mTc-anti-SM-MAb was studied, and scintigraphic imaging with 99mTc-anti-SMMAb was performed in rats immediately after experimental aortic dissection and 1 and 2 wk later. RESULTS: The radioactivity of 99mTc-anti-SM-MAb in the dissected aorta showed a significant increase compared both with the normal portion of the aorta and with blood 6 h after injection of the radiotracer; the ratio of the percentage injected dose per gram (%lD/g) in the lesion to that retained in the normal portion was 4.17 +/- 1.47. Scintigraphic imaging with 99mTc-anti-SM-MAb allowed distinct visualization of the dissected aorta with specific accumulation of antibody 6 h after tracer injection. Selective accumulation of the tracer in the dissected portion of the aorta persisted even 1 wk after aortic injury, allowing clear visualization of the dissected lesion by scintigraphy. CONCLUSION: Radioimmunoscintigraphy using anti-SM-MAb is a potentially useful noninvasive diagnostic method for imaging aortic dissection.
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Journal of human genetics 46(1) 38-40 2001年 査読有りMutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta-Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.
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CIRCULATION RESEARCH 88(1) 30-36 2001年1月Transforming growth factor (TGF)-beta plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-beta on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-beta in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-beta. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-beta at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-beta response element is localized to CAGA motif at -108 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that the binding activity to the CAGA motif was increased in nuclear extracts of cultured VSMCs by TGF-beta. Cells transfected with adenovirus vector expressing CARP showed a significant decrease in DNA synthesis. Overexpression of CARP enhanced the TGF-beta -mediated inhibition of the DNA synthesis. These data indicate that CARP is a downstream target of TGF-beta /Smad signaling in VSMCs and suggest a role of CARP in mediation of the inhibitory effects of TGF-beta on the proliferation of VSMCs.
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Transplantation 70(11) 1653-6 2000年12月15日 査読有りBACKGROUND: We have recently identified basic transcription factor-binding protein 2 (BTEB2), which is involved in phenotypic modulation of vascular vascular smooth muscle cells. The aim of this study was to investigate the expression of BTEB2 in cardiac allograft vascular disease. METHODS: Heterotopic cardiac transplantation was performed in rats. All grafts were stained with antibodies against for BTEB2 and cyclin-dependent kinase 4 for immunohistochemical study. The intensity of BTEB2 expression was also calculated. RESULTS: In the allografts at 4 and 8 weeks after transplantation, smooth muscle cells were positive for BTEB2 in the diffusely thickened coronary arteries and the perivascular space. BTEB2 expression was closely associated with cyclin-dependent kinase 4 expression. The BTEB2 expression score was significantly higher in the allografts compared with the isografts. CONCLUSIONS: The induced expression of BTEB2 may play a potential role in the development of the cardiac allograft vascular disease.
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Circulation 102(23) 2873-9 2000年12月5日 査読有りBACKGROUND: Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress-induced apoptotic death. METHODS AND RESULTS: Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H(2)O(2)). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 micromol/L H(2)O(2) for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, approximately 4% versus H(2)O(2), approximately 23%). Pretreatment with 10(-)(6) mol/L insulin significantly decreased the number of H(2)O(2)-induced TUNEL-positive cardiac myocytes (approximately 12%) and DNA fragmentation induced by H(2)O(2). Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongly activated both PI3K and the putative downstream effector AKT: Moreover, a proapoptotic protein, BAD:, was significantly phosphorylated and inactivated by insulin through PI3K. CONCLUSIONS: These results suggest that insulin protects cardiomyocytes from oxidative stress-induced apoptosis through the PI3K pathway.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 279(2) 582-588 2000年12月Enhanced production of reactive oxygen species plays a role in myocardial injury following ischemia/ reperfusion. Heme oxygenase-1 (HO-1) is a heme-catabolizing enzyme that is induced by and acts against oxidant-induced tissue injury, We examined whether HO-1 expression was regulated following ischemia and reperfusion in the rat heart. HO-1 expression increased as early as 24 h after reperfusion. Strong HO-1 expression was seen in monocytes/ macrophages and myofibroblasts. Next, we examined whether the induction of HO-1 could ameliorate cardiac injury following ischemia/reperfusion. Intraperitoneal hemin injection (30 mg/kg/day) for 2 days prior to the operation resulted in an about 2.8-fold increase in HO-1 expression in the rat heart. Hemin treatment significantly decreased infarct area (6 +/- 2%) compared to the control (21 +/- 2%), which was reversed by the coadministration of an HO inhibitor in a dose-dependent manner. Our data suggest that induction of HO-1 can reduce the cardiac injury in vivo following ischemia/reperfusion. (C) 2000 Academic Press.
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Hypertension (Dallas, Tex. : 1979) 36(6) 934-40 2000年12月 査読有りWe investigated whether an angiotensin-converting enzyme (ACE) inhibitor increases the production of nitric oxide (NO) in exhaled air in normotensive and hypertensive subjects. In study 1, 8 normotensive male subjects received a single oral dose of enalapril (5 mg) or nitrendipine (10 mg) in a crossover manner. Exhaled air was collected at baseline, and at 2, 4, and 8 hours after administration of the drug. In study 2, 10 normotensive subjects (6 men and 4 women) and 10 hypertensive subjects (6 men and 4 women) received a single oral dose of enalapril (5 mg). Exhaled air was collected at baseline and at 2 and 4 hours after administration of the drug. In study 1, enalapril significantly increased the NO release rate from the lung in normotensive subjects (36.9+/-5.1 pmol/s at baseline versus 58.3+/-7.3 pmol/s at 4 hours, P<0.01). Nitrendipine did not change the NO release rate. In study 2, enalapril significantly increased the release of NO from the lung in normotensive subjects (40.4+/-6.0 pmol/s at baseline versus 70. 3+/-11.4 pmol/s at 4 hours, P<0.01) but not in hypertensive subjects. ACE inhibition increased NO production from the lung in normotensive subjects but not in hypertensive patients. The reduction of angiotensin II production and/or the accumulation of bradykinin in the pulmonary tissue may be responsible for increased NO production in components of the lung, such as the pulmonary vascular endothelium, bronchial epithelial cells, macrophages, nasopharyngeal cells, and neurons. However, the effects of ACE inhibition on NO production from the lung differ between hypertensive subjects and normotensive subjects.
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Journal of molecular and cellular cardiology 32(12) 2163-71 2000年12月 査読有りEncephalomyocarditis virus causes viral myocarditis with myocyte necrosis and inflammatory cell infiltration in mice. Because previous studies have shown that some cytokines prevent the sequelae of myocarditis, we assessed the effect of a newly identified cytokine, interleukin-18 (IL-18), in preventing the sequelae of myocarditis. Murine IL-18 (10 microg/day/mouse) was given peritoneally for 10 days in C3H mice infected with EMC virus. Mice were divided into group IL-18 (infected-treated), saline group (infected-untreated), group IL-18-2 (treatment started on day 2), group IL-18-5 (treatment started on day 5). Although the 14-day survival rate in saline group was 20%, that in the group IL-18 increased to 80% (P<0.05). Either mice in group IL-18-2 or in group IL-18-5 did not survive longer than saline group. The viral titer of the heart on day 3 was lower in group IL-18 compared to the saline group (1.00+/-0.20 log(10)tissue culture infected dose (TCID)(50)/mg wet weight v 1.42+/-0.12 log(10)TCID(50)/mg, n=3 of each). Mice in group IL-18 had less myocardial necrosis and cellular infiltration than the saline group. The myocardial expression of interferon- gamma (IFN- gamma) mRNA in group IL-18 was significantly (P<0.05) greater than the saline group on days 1 and 3 after viral inoculation. Circulating IFN- gamma was significantly elevated on days 1, 5, and 7, but significantly reduced on day 3. The natural killer cell activities in the spleen on days 1, 3, and 5 were significantly (P<0.05) greater in group IL-18 than in the saline group (41+/-9%v 10+/-6% on day 3, 4 of each). We conclude that IL-18 reduces the severity of EMC viral myocarditis by inducing cardiac expression of IFN- gamma mRNA and increasing splenic natural killer cell activity.
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Circulation 102(20) 2528-34 2000年11月14日 査読有りBACKGROUND: We have previously shown BTEB2, a Krüppel-like zinc finger transcription factor, to regulate expression of the SMemb/NMHC-B gene, which has been implicated in phenotypic modulation of smooth muscle cells (SMCs). The present study was done to assess the developmental and pathological expression profiles of BTEB2 and to further evaluate the clinical relevance of BTEB2 expression in human coronary artery disease. METHODS AND RESULTS: Immunohistochemistry showed developmentally regulated expression of BTEB2 with abundant expression in fetal but not in adult aortic SMCs of humans and rabbits. In balloon-injured aortas, predominant expression of BTEB2 was seen in neointimal SMCs. Atherectomy specimens obtained from primary and restenotic lesions showed predominant expression of BTEB2 to stellate SMCs. The incidence of restenosis in primary lesions was significantly higher in lesions containing BTEB2-positive cells than in lesions without (55.6% versus 25.0%, P:=0.01). CONCLUSIONS: The present study shows that BTEB2 expression is developmentally and pathologically regulated. BTEB2 is preferentially expressed in dedifferentiated or activated SMCs. Examination of human coronary artery specimens suggests that primary lesions containing BTEB2-positive cells are associated with higher risk of restenosis than BTEB2-negative lesions. These results suggest that BTEB2 can serve as a molecular marker for phenotypic modulation of vascular SMCs.
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The Journal of biological chemistry 275(45) 35291-6 2000年11月10日 査読有りA homeodomain-containing transcription factor Csx/Nkx-2.5 is an important regulator of cardiogenesis in mammals. Three different mutants, Gln170ter (designated A) and Thr178Met (designated B) in the helix 2 of the homeodomain and Gln198ter mutation (designated C) just after homeodomain, have been reported to cause atrial septal defect with atrial ventricular block. We here examined the functions of these three mutants of Csx/Nkx-2.5. The atrial natriuretic peptide (ANP) promoter was activated by wild type Csx/Nkx-2.5 (WT, approximately 8-fold), B ( approximately 2-fold), and C ( approximately 6-fold) but not by A. When A, B, or C was cotransfected into COS-7 cells with the same amount of WT, WT-induced activation of the ANP promoter was attenuated by A and B (A > B), whereas C further enhanced the activation. Immunocytochemical analysis using anti-Myc tag antibody indicated that transfected Myc-tagged WT, B, and C were localized in the nucleus of both COS-7 cells and cardiomyocytes of neonatal rats, whereas A was distributed diffusely in the cytoplasm and nucleus in COS-7 cells. Electrophoretic mobility shift assay showed that Csx/Nkx-2.5-binding sequences were bound strongly by WT and C, weakly by B, but not by A. Immunoprecipitation and GST pull-down assay revealed that WT and all mutants interacted with GATA-4. The synergistic activation of the ANP promoter by WT and GATA-4 was further enhanced by C but was inhibited by A and B. In the cultured cardiomyocytes, overexpression of C but not WT, A, or B, induced apoptosis. These results suggest that although the three mutants induce the same cardiac phenotype, transactivation ability and DNA binding ability are different among the three mutants and that apoptosis may be a cause for C-induced cardiac defect.
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The Journal of biological chemistry 275(44) 34528-33 2000年11月3日 査読有りApoptosis of cardiac myocytes is one of the causes of heart failure. Here we examine the mechanism by which the activation of beta-adrenergic receptor induces cardiomyocyte apoptosis. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling and DNA ladder analyses revealed that isoproterenol (Iso) induced the apoptosis of cardiac myocytes of neonatal rats through an increase in intracellular Ca(2+) levels. The Iso-induced cardiomyocyte apoptosis was strongly inhibited by the L-type Ca(2+) channel antagonist nifedipine and by the calcineurin inhibitors cyclosporin A and FK506. Iso reduced the phosphorylation levels of the proapoptotic Bcl-2 family protein Bad and induced cytochrome c release from mitochondria to the cytosol through calcineurin activation. Infusion of Iso increased calcineurin activity by approximately 3-fold in the hearts of wild-type mice but not in the hearts of transgenic mice that overexpress dominant negative mutants of calcineurin. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling analysis revealed that infusion of Iso induced apoptosis of cardiac myocytes and that the number of apoptotic cardiomyocytes was significantly less in the hearts of the transgenic mice compared with the wild-type mice. These results suggest that calcineurin plays a critical role in Iso-induced apoptosis of cardiac myocytes, possibly through dephosphorylating Bad.
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JAPANESE HEART JOURNAL 41(6) 767-772 2000年11月In a patient with Wolff-Parkinson-White syndrome whose accessory pathway was primarily capable of bidirectional conduction, antegrade conduction over the accessory pathway was transiently inhibited after rapid atrial or ventricular pacing or after spontaneous termination of atrioventricular reentrant tachycardia. Pacing rate and duration of tachycardia were related to the duration of the suppression of preexcitation, while the coupling interval of the first sinus beat to the last driven or tachycardia beat was irrelevant to the phenomenon. Thus, overdrive suppression of conduction may be the most likely mechanism of this phenomenon.
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JAPANESE HEART JOURNAL 41(6) 713-721 2000年11月Prolonged QT interval is suggested to indicate an increased risk of sudden cardiac death in certain clinical conditions such as diabetes mellitus. We investigated whether the individual QT interval is an indicator of an autonomic state. An ambulatory 24-hour ECG was recorded in 53 subjects from different clinical backgrounds. Power spectral components of heart rate variability (HRV) and the QT interval were regressively obtained at a heart rate of 60, 70, 80, 90, or 100 beats per minutes (bpm). Log values of the high-frequency component of HRV (HF: 0.15-0.50 Hz, a scale of cardiac parasympathetic tone) failed to show a relationship with the QT interval. In contrast, the QT interval at a heart rate of 90 bpm and I00 bpm showed a significant correlation with the log Values of the low-frequency component (LF: 0.04-0.15 Hz) and the log[LF / HF], i.e., a putative scale of sympathetic tone (100 bpm: QT vs logLF: r = 0.414, p < 0.005, QT vs log[LF / HF]: r = 0.416, p < 0.002). Also, attenuated rate-dependent QT shortening was associated with greater logLF and log[LF / HF] values at a heart rate of 80, 90, or 100 bpm. These results suggest that the QT interval at a moderate heart rate (approximately 90-100 / min) and the degree of rate-dependent QT shortening are related to individual sympathetic tone.
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TRANSPLANTATION PROCEEDINGS 32(7) 1786-1788 2000年11月
書籍等出版物
21-
Springer 2009年 (ISBN: 9784431877745)
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Signal Transduction and Cardiac Hypertrophy (Naranjan S. Dhalla, Larry Hryshko, Elissavet Kardami, Pawan K. Singal, KLUWER ACADEMIC PUBLISHERS) 2003年
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Signal Transduction and Cardiac Hypertrophy (Naranjan S. Dhalla, Larry Hryshko, Elissavet Kardami, Pawan K. Singal, KLUWER ACADEMIC PUBLISHERS) 2003年
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Rapid Cycle Real-Time PCR : methods and applications 2001年
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in"The Hypertrophied Heart" 2000年
共同研究・競争的資金等の研究課題
91-
日本学術振興会 科学研究費助成事業 2023年4月 - 2026年3月
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日本学術振興会 科学研究費助成事業 2020年7月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2019年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2019年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2018年6月 - 2023年3月