研究者詳細 - 廣畑　聡

Chromosomal mapping of Adam9, Adam15 and Adam21."jointly worked"

Matrix Biol. May;19(2):185-7 ( 2 ) 185 - 187 2000年5月

ADAM-TS8, a novel metalloprotease of the ADAM-TS family located on mouse chromosome 9 and human chromosome 11."jointly worked"

Genomics. Dec 1;62(2):312-5 ( 2 ) 312 - 315 1999年12月

ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family."jointly worked"

J Biol Chem. Sep 3;274(36):25555-63 ( 36 ) 25555 - 25563 1999年9月

Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively."jointly worked"

Genomics. Jul 1;51(1):148-51 ( 1 ) 148 - 151 1998年7月

Time-dependent alterations of serum levels of triple-helix domain and 7S domain of type IV collagen in patients with acute myocardial infarction after successful reperfusion: Limited relation to left ventricular ejection fraction

Y Kajikawa, S Kusachi, J Kondo, Sano, I, K Yamamoto, S Hirohata, M Murakami, T Murakami, T Tsuji

CLINICA CHIMICA ACTA 258 ( 2 ) 241 - 247 1997年2月

Laminin alpha 1, alpha 2, alpha 4 and beta 1 chain mRNA expression in mouse embryonic, neonatal, and adult hearts.

Jpn Heart J. Mar;38(2):281-9 ( 2 ) 281 - 289 1997年

Time dependent alterations of serum matrix metalloproteinase-1 and metalloproteinase-1 tissue inhibitor after successful reperfusion of acute myocardial infarction

Satoshi Hirohata, Shozo Kusachi, Masahiro Murakami, Takashi Murakami, Issei Sano, Tomoko Watanabe, Issei Komatsubara, Jun Kondo, Takao Tsuji

Heart 78 ( 3 ) 278 - 284 1997年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ Publishing Group

Objective - To test the hypothesis that changes in serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) after acute myocardial infarction reflect extracellular matrix remodelling and the infarct healing process. Patients - 13 consecutive patients with their first acute myocardial infarction who underwent successful reperfusion. Methods - Blood was sampled on the day of admission, and on days 2, 3, 4, 5, 7, 14, and 28. Serum MMP-1 and TIMP-1 were measured by one step sandwich enzyme immunoassay. Left ventricular volume indices were determined by left ventriculography performed four weeks after the infarct. Results - Serum concentrations of both MMP-1 and TIMP-1 changed over time. The average serum MMP-1 was more than 1 SD below the mean control values during the initial four days, increased thereafter, reaching a peak concentration around day 14, and then returned to the middle control range. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum MMP-1 on day 5, when it began to rise, and for the magnitude of rise in MMP-1 on day 5 compared to admission. Serum TIMP-1 at admission was more than 1 SD below the mean control value, and increased gradually thereafter, reaching a peak on around day 14. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum TIMP-1 on days 5 and 7, and for the magnitude of rise in TIMP-1 on days 5 and 7 compared to admission. Conclusions -Both MMP-1 and TIMP-1 showed significant time dependent alteration after acute myocardial infarction. Thus MMP-1 and TIMP-1 may provide useful information in evaluating the healing process as it affects left venticular remodelling after acute myocardial infarction.

DOI： 10.1136/hrt.78.3.278

Tenascin expression in endomyocardial biopsy specimens in patients with dilated cardiomyopathy: Distribution along margin of fibrotic lesions

Akiko Tamura, Shozo Kusachi, Kunio Nogami, Asami Yamanishi, Yutaka Kajikawa, Satoshi Hirohata, Takao Tsuji

Heart 75 ( 3 ) 295 - 300 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ Publishing Group

Objective - To examine the hypothesis that tenascin, an extracellular matrix glycoprotein, contributes to fibrotic changes in dilated cardiomyopathy. Methods - The localisation of tenascin in biopsy specimens of the hearts obtained from eight patients with dilated cardiomyopathy was examined using staining by the avidin-biotin-peroxidase complex method Results - (1) Perimysium and endomysium. Although positive staining for tenascin was observed in the enlarged perimysium and endomysium in all patients, moderately intense staining was characteristically observed near the replacement fibrotic lesions. In the narrow perimysium and endomysium of the myocardium not containing replacement fibrotic lesions, tenascin was not present, as in the control specimens. (2) Replacement fibrotic lesions. Non-homogeneous positive staining for tenascin was detected in all replacement fibrotic lesions examined. Intense tenascin deposition was observed in the peripheral portion of the replacement fibrotic lesions. The tenascin staining observed in the small replacement fibrotic lesions was more intense than that in the large lesions. Conclusions - Tenascin contributes to the development of the fibrotic changes seen in the dilated cardiomyopathic heart. Its characteristic location, specifically the distribution along the margin of the fibrosis, suggests that fibrotic change is a continuous process in hearts with dilated cardiomyopathy.

DOI： 10.1136/hrt.75.3.291

Reperfusion hastens appearance and extent of distribution of type I collagen in infarct zone: Immunohistochemical study in rat experimental infarction

S. Yamasaki, S. Kusachi, H. Moritani, J. Kondo, S. Hirohata, A. Tamura, T. Tsuji

Cardiovascular Research 30 ( 5 ) 763 - 768 1995年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background: The effects of reperfusion on time-dependent alteration of type I collagen have not been examined. Objectives: We compared the sequential changes in the appearance and distribution of type I collagen in reperfused infarct rat hearts to those in non-reperfused hearts. Methods: Using an experimental rat model of infarction, we performed immunohistochemical staining with a polyclonal antibody to type I collagen by the avidin-biotin-peroxidase method. Reperfusion was established after 2-h coronary ligation that produced complete necrosis of myocytes. Results: In reperfused hearts, type I collagen appeared in the peripheral zone of the infarct at day 2, which was 1 day earlier than in non-reperfused hearts. The extent of distribution of type I collagen in reperfused hearts was comparable to that observed approximately 1 day later in non-reperfused hearts. Conclusion: Reperfusion can accelerate collagen matrix formation compared with that in non-reperfused hearts after acute myocardial infarction.

DOI： 10.1016/0008-6363(95)00116-6

Distribution and Incorporation of Extracellular Vesicles into Chondrocytes and Synoviocytes 査読

Takashi Ohtsuki, Ikumi Sato, Ren Takashita, Shintaro Kodama, Kentaro Ikemura, Gabriel Opoku, Shogo Watanabe, Takayuki Furumatsu, Hiroshi Yamada, Mitsuru Ando, Kazunari Akiyoshi, Keiichiro Nishida, Satoshi Hirohata

International Journal of Molecular Sciences 25 ( 22 ) 11942 2024年11月

Efficacy and safety of a novel temperature-controlled catheter for cavotricuspid isthmus ablation. 査読国際誌

Masaya Sano, Hirosuke Yamaji, Shunichi Higashiya, Motoki Kubo, Takashi Murakami, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

Journal of cardiovascular electrophysiology 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Maintaining an adequate temperature at the target site is essential for effective ablation. We hypothesized that a tissue temperature-controlled (T-Con) catheter for cavotricuspid isthmus (CTI) ablation could improve the procedural ablation parameters. PURPOSE: To evaluate the efficacy and safety of the T-Con (DiamondTemp™) catheter for CTI ablation compared with non-irrigation (Non-Irri) and irrigation (Irri) catheters. METHODS: We analyzed 150 patients who underwent prophylactic CTI ablation combined with pulmonary vein isolation. The Non-Irri, Irri, and T-Con catheter groups comprised 50 patients each, and the ablation procedural parameters and complications were compared between these groups. RESULTS: There were no significant differences in clinical background characteristics among the three groups. The Kruskal-Wallis and post hoc tests demonstrated that the T-Con group showed the lowest total radiofrequency energy delivery time among the three groups (median [25 and 75 percentiles]: 340 [209, 357], 147 [100, 199], and 83 [61, 109] s, respectively in the Non-Irri, Irri, and T-Con groups; T-Con versus Non-Irri, p < .01; T-Con versus Irri, p < .01). The total procedural time and acute reconnection rate in the T-Con group (264 s and 4%, respectively) were lower than those in the Non-Irri group (438 s and 24%) but were similar to those in the Irri group (268 s and 6%). No significant complications were observed in any group. CONCLUSIONS: The T-Con catheter achieved a short energy delivery time and a low acute reconnection rate, indicating its potential as an alternative catheter for CTI ablation.

DOI： 10.1111/jce.16378

Uric Acid Elevation by Fructose Overload Exacerbates Nash and Atherosclerosis via Oxidative Stress 査読

Moe Fujii, Mai Kakimoto, Ikumi Sato, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoshi Hirohata, Kazuya Kitamori, Shang Ran, Shusei Yamamoto, Shogo Watanabe

Current Nutrition and Food Science 20 ( 2 ) 250 - 261 2024年

掲載種別：研究論文（学術雑誌）

Background: Nonalcoholic steatohepatitis (NASH) is well associated with an increased risk of cardiovascular disease (CVD), regardless of risk factors for metabolic syndrome. However, intermediary factors between NASH and CVD remain unknown. In recent years, hyperuricemia has been associated not only with gout but also with several other organ diseases, such as hypertension, chronic renal failure, and metabolic syndrome. In addition, hyperuricemia was shown to frequently occur in patients with NASH and could be a risk factor for CVD. Furthermore, serum uric acid (UA) levels have been linked with fructose intake. Objectives: We hypothesized that fructose loading elevates UA levels and exacerbates NASH and atherosclerosis via oxidative stress. Methods: Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr), between 14 to 24 weeks of age, were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet. In addition to the HFC diet, the fructose group was subjected to 10% fructose loading. The oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed at 25-week-old, followed by blood sampling, animal sacrifice, endothelial function test, blood biochemistry, histopathological staining, xanthine oxidase activity test, and genetic analysis performed at 26-week-old. Results: Fructose loading increased UA and oxidative stress levels. In addition, fructose loading induced insulin resistance. The fructose group exhibited aggravated hepatic fibrosis and lipid depo-sition, as well as enhanced lipid accumulation in the mesenteric arteries. Conclusion: In the SHRSP5/Dmcr rat model, elevated UA levels were a risk factor for the exacer-bation of NASH and atherosclerosis via oxidative stress.

DOI： 10.2174/1573401319666230508150159

Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model. 査読国際誌

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoru Tamura, Minoru Ueda, Satoshi Hirohata, Shogo Watanabe

Canadian journal of physiology and pharmacology 101 ( 9 ) 455 - 465 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Canadian Science Publishing

The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRβ, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRβ-specific agonist. We aimed to examine whether OBG specifically affects LXRβ in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (－) group, and (IV) OBG (+) group. All groups’ rats were intraperitoneally administered L-NAME. The L-NAME/OBG groups’ rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) groups’ rats were administered OBG, while the OBG (－) groups’ rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRβ-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.

DOI： 10.1139/cjpp-2022-0532

SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet develop disease-induced sarcopenia as nonalcoholic steatohepatitis progresses. 査読国際誌

Shusei Yamamoto, Koki Honma, Moe Fujii, Mai Kakimoto, Sora Kirihara, Hinako Nakayama, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Shogo Watanabe

Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 249 152104 - 152104 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Secondary sarcopenia develops as a result of a bedridden state and illnesses, such as cachexia, liver disease, and diabetes. However, there is a lack of animal models to investigate the underlying mechanisms and potential treatments for secondary sarcopenia. Recently, secondary sarcopenia has been associated with the prognosis of nonalcoholic steatohepatitis. This study aimed to investigate whether stroke-prone spontaneously hypertensive rat 5 (SHRSP5/Dmcr) which developed severe nonalcoholic steatohepatitis by a high-fat and high-cholesterol (HFC; containing 2% cholic acid) diet is a useful model of secondary sarcopenia. METHODS: SHRSP5/Dmcr rats were divided into 6 groups fed with a Stroke-Prone (SP: normal chow) or HFC diets for different periods (4, 12, and 20 weeks), and WKY/Izm rats were divided into 2 groups fed an SP or HFC diet. Body weight, food intake, and muscle force were measured weekly for all rats. After the end of the diet period, skeletal muscle strength evoked by electrical stimulation was recorded, blood was collected, and organ weight was measured. The sera were used for biochemical analysis and the organs were used for histopathological analysis. RESULTS: SHRSP5/Dmcr rats fed an HFC diet developed nonalcoholic steatohepatitis, and their skeletal muscles, especially fast muscles, showed atrophy, indicating that muscle atrophy is aggravated by the progression of nonalcoholic steatohepatitis. In contrast, WKY/Izm rats fed an HFC diet did not exhibit sarcopenia. CONCLUSIONS: This study suggests that SHRSP5/Dmcr rats could be a useful novel model for investigate the mechanism of secondary sarcopenia disorder associated with nonalcoholic steatohepatitis.

DOI： 10.1016/j.aanat.2023.152104

Evidence for Hypoxia-Induced Shift in ATP Production from Glycolysis to Mitochondrial Respiration in Pulmonary Artery Smooth Muscle Cells in Pulmonary Arterial Hypertension. 査読国際誌

Satoshi Akagi, Kazufumi Nakamura, Megumi Kondo, Satoshi Hirohata, Heiichiro Udono, Mikako Nishida, Yukihiro Saito, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

Journal of clinical medicine 12 ( 15 ) 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The metabolic state of pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) is not well understood. In this study, we examined the balance between glycolysis and mitochondrial respiration in non-PAH-PASMCs and PAH-PASMCs under normoxia and hypoxia. METHODS: We investigated the enzymes involved in glycolysis and mitochondrial respiration, and studied the two major energy-yielding pathways (glycolysis and mitochondrial respiration) by measuring extracellular acidification rate (ECAR) and cellular oxygen consumption rate (OCR) using the Seahorse extracellular flux technology. RESULTS: Under both normoxia and hypoxia, the mRNA and protein levels of pyruvate dehydrogenase kinase 1 and pyruvate dehydrogenase were increased in PAH-PASMCs compared with non-PAH-PASMCs. The mRNA and protein levels of lactate dehydrogenase, as well as the intracellular lactate concentration, were also increased in PAH-PASMCs compared with non-PAH-PASMCs under normoxia. However, these were not significantly increased in PAH-PASMCs compared with non-PAH-PASMCs under hypoxia. Under normoxia, ATP production was significantly lower in PAH-PASMCs (59 ± 5 pmol/min) than in non-PAH-PASMCs (70 ± 10 pmol/min). On the other hand, ATP production was significantly higher in PAH-PASMCs (31 ± 5 pmol/min) than in non-PAH-PASMCs (14 ± 3 pmol/min) under hypoxia. CONCLUSIONS: There is an underlying change in the metabolic strategy to generate ATP production under the challenge of hypoxia.

DOI： 10.3390/jcm12155028

Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis. 査読国際誌

Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Toshiaki Ohara, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Moe Fujii, Shusei Yamamoto, Shang Ran, Shogo Watanabe

Experimental biology and medicine (Maywood, N.J.) 248 ( 13 ) 1112 - 1123 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH.

DOI： 10.1177/15353702231191197

Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats. 査読国際誌

Mai Kakimoto, Moe Fujii, Ikumi Sato, Koki Honma, Hinako Nakayama, Sora Kirihara, Taketo Fukuoka, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Shusei Yamamoto, Shogo Watanabe

Journal of applied biomedicine 21 ( 2 ) 80 - 90 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Xanthine oxidase (XO) generates reactive oxygen species during uric acid production. Therefore, XO inhibitors, which suppress oxidative stress, may effectively treat non-alcoholic steatohepatitis (NASH) and atherosclerosis via uric acid reduction. In this study, we examined the antioxidant effect of the XO inhibitor febuxostat on NASH and atherosclerosis in stroke-prone spontaneously hypertensive 5 (SHRSP5/Dmcr) rats. METHODS: SHRSP5/Dmcr rats were divided into three groups: SHRSP5/Dmcr + high-fat and high-cholesterol (HFC) diet [control group, n = 5], SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) [fructose group, n = 5], and SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) + febuxostat (1.0 mg/kg/day) [febuxostat group, n = 5]. Glucose and insulin resistance, blood biochemistry, histopathological staining, endothelial function, and oxidative stress markers were evaluated. RESULTS: Febuxostat reduced the plasma uric acid levels. Oxidative stress-related genes were downregulated, whereas antioxidant factor-related genes were upregulated in the febuxostat group compared with those in the fructose group. Febuxostat also ameliorated inflammation, fibrosis, and lipid accumulation in the liver. Mesenteric lipid deposition decreased in the arteries, and aortic endothelial function improved in the febuxostat group. CONCLUSIONS: Overall, the XO inhibitor febuxostat exerted protective effects against NASH and atherosclerosis in SHRSP5/Dmcr rats.

DOI： 10.32725/jab.2023.009