研究者詳細 - 三好　亨

論文 - 三好　亨

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Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice. 国際誌

Toru Miyoshi, Yuhua Li, Diana M Shih, Xuping Wang, Victor E Laubach, Alan H Matsumoto, Gregory A Helm, Aldons J Lusis, Weibin Shi

Life sciences 79 ( 6 ) 525 - 31 2006年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The inducible nitric oxide synthase (iNOS) is abundantly expressed by smooth muscle cells and macrophages in atherosclerotic lesions. Apolipoprotein E-deficient (apoE(-/-)) mice develop early and advanced atherosclerotic lesions. The role of iNOS in both early and advanced atherosclerotic formation was determined in apoE(-/-) mice. Mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 12 weeks of age on chow diet, iNOS(-/-)/apoE(-/-) mice developed comparable sizes of early atherosclerotic lesions in the aortic root as did iNOS(+/+)/apoE(-/-) mice (30,993+/-4746 vs. 26,648+/-6815 microm(2)/section; P=0.608). After being fed the Western diet for 12 weeks, iNOS(-/-)/apoE(-/-) mice developed significantly smaller advanced lesions than iNOS(+/+)/apoE(-/-) mice (458,734+/-14,942 vs. 519,570+/-22,098 microm(2)/section; P=0.029). This reduction in lesion formation could not be explained by differences in plasma lipid levels. To examine whether iNOS contributed to LDL oxidation, smooth muscle cells were isolated from the aorta, activated with TNF-alpha, and then incubated with native LDL in the absence or presence of N-Omega-nitro-L-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by smooth muscle cells from iNOS(+/+)/apoE(-/-) mice (P=0.048), but it had no effect on LDL oxidation by cells from iNOS(-/-)/apoE(-/-) mice. iNOS(-/-)/apoE(-/-) mice had a significantly lower plasma lipoperoxide level on the Western diet (2.74+/-0.23 vs. 3.89+/-0.41 microM MDA; P=0.021) but not on chow diet (1.02+/-0.07 vs. 1.51+/-0.29 microM MDA; P=0.11). Thus, the absence of iNOS-mediated LDL oxidation may contribute to the reduction in advanced lesion formation of iNOS(-/-)/apoE(-/-) mice.

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Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion. 国際誌

Satoshi Sezaki, Satoshi Hirohata, Akihiro Iwabu, Keigo Nakamura, Kenichi Toeda, Toru Miyoshi, Hitoshi Yamawaki, Kadir Demircan, Shozo Kusachi, Yasushi Shiratori, Yoshifumi Ninomiya

Experimental biology and medicine (Maywood, N.J.) 230 ( 9 ) 621 - 30 2005年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Thrombospondin-1 (TSP-1) is a multifunctional, rapid-turnover matricellular protein. Recent studies demonstrated that TSP-1 has a role in regulating inflammatory reactions. Myocardial infarction (MI) is associated with an inflammatory response, ultimately leading to healing and scar formation. In particular, an enhanced inflammatory reaction and a massive accumulation of monocytes/macrophages is seen with reperfusion after MI. To examine the role of TSP-1 in MI, we isolated rat TSP-1 complementary DNA (cDNA) and analyzed the level and distribution of the mRNA expression. In infarcted rat hearts, TSP-1 mRNA increased markedly at 6 and 12 hrs after coronary artery ligation (27.97 +/- 3.40-fold and 22.77 +/- 1.83-fold, respectively, compared with sham-operated hearts). Western blot analysis revealed that TSP-1 protein was transiently induced in the infarcted heart. Using in situ hybridization analysis, TSP-1 mRNA signals were observed in the infiltrating cells at the border area of infarction. We then examined the effect of ischemia/reperfusion (I/R) on TSP-1 mRNA induction in the rats with infarcted hearts. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that I/R enhanced the TSP-1 mRNA expression approximately 4-fold, as compared with the level in the permanently ligated heart. Finally, we examined the effect of TSP-1 on proinflammatory cytokine release in mononuclear cells. The releases of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from human mononuclear cells were enhanced by TSP-1 in a dose-dependent manner. Thus, the immediate and marked increase of TSP-1 expression suggests that TSP-1 has an inflammatory-associated role in MI.

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Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status. 国際誌

Hideaki Ito, Takao Kanzawa, Toru Miyoshi, Satoshi Hirohata, Satoru Kyo, Arifumi Iwamaru, Hiroshi Aoki, Yasuko Kondo, Seiji Kondo

Human gene therapy 16 ( 6 ) 685 - 98 2005年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

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Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. 国際誌

Chisato Suezawa, Shozo Kusachi, Takashi Murakami, Kenichi Toeda, Satoshi Hirohata, Keigo Nakamura, Keizo Yamamoto, Kazuya Koten, Toru Miyoshi, Yasushi Shiratori

The Journal of laboratory and clinical medicine 145 ( 1 ) 33 - 40 2005年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteopontin is a secreted extracellular-matrix glycoprotein that plays a role in the healing of remodeling tissue. We examined the relationship of plasma osteopontin levels with left-ventricular (LV) volume and function in 18 consecutive patients who underwent successful reperfusion after anterior-wall acute myocardial infarction (AMI). The plasma osteopontin level was within the control range at admission (mean +/- SD 420 +/- 195 ng/mL), began to increase on day 2 (935 +/- 464 ng/mL), and reached a maximum around day 3 (1139 +/- 482 ng/mL). The level remained high on days 4, 5, and 7 ( approximately 1000 ng/mL) and then decreased on day 14. Maximal plasma osteopontin levels and the difference between maximal and minimal levels were positively correlated with LV end-systolic volume index (r = .58, P < .05; and r = .65, P < .01, respectively) and negatively correlated with LV ejection fraction (r = -.52, P < .05; and r = -.60, P < .01, respectively). The area under the curve of plasma osteopontin levels for 14 days after AMI was significantly correlated with LV end-systolic volume index (r = .66, P < .01), LV end-diastolic volume index (r = .50, P < .05), and LV ejection fraction (r = -.55, P < .05). In subgroup patients with the same area of risk for myocardial infarction (ie, responsible lesions located at the same proximal left anterior descending coronary artery), essentially the same or a closer relationship between plasma osteopontin level and LV volume and function was noted. Plasma osteopontin levels were correlated substantially with plasma levels of high-sensitivity C-reactive protein (hsCRP) and weakly with serum creatine kinase release. In conclusion, the plasma level of osteopontin changes in a time-dependent fashion and is correlated with LV volumes and function and associated substantially with the extent of the inflammatory response indicated by the plasma hsCRP level and weakly with infarct size estimated on the basis of cardiac-enzyme release.

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Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction. 国際誌

Keigo Nakamura, Satoshi Hirohata, Takashi Murakami, Toru Miyoshi, Kadir Demircan, Toshitaka Oohashi, Hiroko Ogawa, Kazuya Koten, Kenichi Toeda, Shozo Kusachi, Yoshifumi Ninomiya, Yasushi Shiratori

Journal of biochemistry 136 ( 4 ) 439 - 46 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.

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Circulating white blood cell count correlates with left ventricular indices independently of the extent of risk area for myocardial infarction after successful reperfusion. 国際誌

Tadahisa Uesugi, Kohichiro Iwasaki, Masaaki Murakami, Keizo Yamamoto, Shozo Kusachi, Takashi Murakami, Masanari Obika, Shigeshi Kamikawa, Toru Miyoshi, Yasushi Shiratori

Acta cardiologica 59 ( 5 ) 533 - 9 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To test the hypothesis that the circulating white blood cell (WBC) and neutrophil counts are related to left ventricular (LV) indices in patients with the same risk area for acute myocardial infarction (AMI), we examined 100 consecutive AMI patients who had the culprit lesion at segment 6 according to the American Heart Association classification and who underwent successful direct coronary angioplasty. METHODS AND RESULTS: The LV ejection fraction (LVEF), end-systolic volume (LVESVI) and end-diastolic volume index (LVEDVI) were obtained by left ventriculography performed 4 weeks after AMI onset. Univariate analysis disclosed that the counts of WBC and neutrophils on admission, and the maximal WBC count correlated negatively with LVEF (r = -0.46, p < 0.001; r = -0.54, p < 0.001 and r = -0.40, p < 0.001, respectively) and positively with LVESVI (r = 0.43, p < 0.001; r = 0.55, p < 0.001, and r = 0.30, p < 0.01, respectively). The counts of WBC and neutrophils on admission also correlated with LVEDVI (r = 0.28, p < 0.01 and r = 0.41, p < 0.001, respectively). Multivariate analysis with other clinical and angiographic factors revealed that the counts of WBC and neutrophils on admission correlated with LVEF (partial correlation coefficient, r = -0.37, p < 0.001 and r = -0.52, p < 0.001, respectively), with LVESVI (r = 0.34, p < 0.01 and r = 0.56, p < 0.001, respectively) and with LVEDVI (r = 0.28, p < 0.01 and r = 0.44, p < 0.001, respectively). The maximal WBC count also correlated with LVEF and LVESVI (r = -0.40, p < 0.001 and r = 0.21, p < 0.05, respectively). CONCLUSION: The present study revealed that the circulating WBC count correlated with function and volume of the successfully reperfused LV after AMI in patients with the same risk area for AMI, indicating that the WBC count needs to be taken into consideration as an independent factor affecting the LV indices.

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新規ラットlink protein geneの同定と特性 Lp3/Hapln3(Identification and Characterization of a novel rat link protein gene: Lp3/Hapln3)

小川弘子, 廣畑聡, 三好亨, 村上充, 白鳥康史, 大橋俊孝, 二宮善文, 草地省蔵, 佐田政隆

Circulation Journal 68 ( Suppl.III ) 938 - 938 2004年10月

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