Shinji Takai

Publications (190) View all

• Article: PIVOTAL ROLE OF MOUSE MAST CELL PROTEASE 4 IN THE CONVERSION AND PRESSOR PROPERTIES OF BIG-ENDOTHELIN-1.

  Martin Houde, Marc-David Jamain, Julie Labonte, Louisane Desbiens, Gunnar Pejler, Michael Gurish, Shinji Takai, Pedro D'Orleans-Juste
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  ABSTRACT: The serine protease chymase has been reported to generate intra-cardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin (ET)-1, ET-1 (1-31) from Big-ET-1. While humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between WT and mMCP-4(-/-) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive ET-1 (1-31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (-/-) mice when compared to WT controls. Residual responses to Big-ET-1 in mMCP-4(-/-) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor, thiorphan, and the specific chymase inhibitor, TY-51469 (2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl) sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid). Soluble fractions from the lungs, left cardiac ventricle, aorta and kidneys of WT but not mMCP-4(-/-) mice generated ET-1 (1-31) from exogenous Big-ET-1 in a TY-41569-sensitive fashion as detected by HPLC/MALDI-mass spectrometry. Finally, pulmonary endogenous levels of immunoreactive-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(-/-) mice when compared to WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.
  Journal of Pharmacology and Experimental Therapeutics 04/2013; · 3.83 Impact Factor
• Article: Chymase Inhibition Attenuates Monocrotaline-Induced Sinusoidal Obstruction Syndrome in Hamsters.

  Shinsuke Masubuchi, Koji Komeda, Shinji Takai, Denan Jin, Keitaro Tashiro, Zhong-Lian Li, Yoshinori Otsuki, Haruki Okamura, Michihiro Hayashi, Kazuhisa Uchiyama
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  ABSTRACT: Chymase stored in mast cells activates matrix metalloproteinase (MMP)-9, which may relate to the progression of sinusoidal obstruction syndrome (SOS). We investigated the preventive effect of a chymase inhibitor, TY-51469, on monocrotaline-induced SOS in hamsters. Hamsters were orally administrated with a single dose of monocrotaline (120 mg/kg) to induce SOS. Treatment with TY-51469 (1 mg/kg per day) or placebo was started 3 days before the monocrotaline administration. Two days after the monocrotaline administration, significant increases of aspartate aminotransferase, alanine aminotransferase and total bilirubin and a significant reduction of albumin were observed in plasma, but their changes were significantly attenuated by treatment with TY-51469. The numerous hepatic necrosis areas were observed in the placebo-treated group, but the ratio of necrotic area to total area in liver was significantly reduced by treatment with TY-51469. Both chymase activity and MMP-9 level in liver were significantly augmented in the placebo-treated group. Furthermore, tumor necrosis factor (TNF)-α level in liver was also augmented in the placebo-treated group. However, the chymase activity and levels of MMP-9 and TNF-α were significantly attenuated in the TY-51469-treated group. Until 14 days after monocrotaline administration, survival rates in the placebo- and TY-51469-treated groups were 25% and 70%, respectively, and there was a significant different. In conclusion, chymase inhibition by TY-51469 may prevent the accelerating of severity in monocrotaline-induced SOS in hamsters.
  Current Medicinal Chemistry 03/2013; · 4.86 Impact Factor
• Article: Chymase inhibitor ameliorates hepatic steatosis and fibrosis on established non-alcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet.

  Shinsuke Masubuchi, Shinji Takai, Denan Jin, Keitaro Tashiro, Koji Komeda, Zhong-Lian Li, Yoshinori Otsuki, Haruki Okamura, Michihiro Hayashi, Kazuhisa Uchiyama
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  ABSTRACT: AIM: Chymase plays a role in the augmentation of angiotensin II formation, which is involved in liver fibrosis. The therapeutic effects of a chymase inhibitor, TY-51469, on established hepatic steatosis and fibrosis were investigated in a model of developed non-alcoholic steatohepatitis. METHODS: Hamsters were fed a normal diet or methionine- and choline-deficient (MCD) diet for 12 weeks. Then, treatment with TY-51469 (1 mg/kg per day) or placebo was initiated, and the treatment was continued concurrently with the MCD diet for an additional 12 weeks. RESULTS: At 12 weeks after initiating the MCD diet, marked hepatic steatosis and fibrosis were observed in MCD diet-fed hamsters. Malondialdehyde and gene expression levels of collagen I, collagen III, α-smooth muscle actin (α-SMA) and Rac-1 in liver extracts were also increased in the MCD-diet-fed hamsters at 12 weeks. At 24 weeks, hepatic steatosis and fibrosis were more prominent in the placebo-treated hamsters that were fed the MCD-diet for 24 weeks versus 12 weeks. Hamsters treated with TY-51469 for 12 weeks after being on a 12-week MCD diet had significant ameliorations in both hepatic steatosis and fibrosis, and there were no significant differences compared to normal diet-fed hamsters. There were significant augmentations in angiotensin II and malondialdehyde, and gene expressions of collagen I, collagen III, α-SMA and Rac-1 in the placebo-treated hamsters at 24 weeks; however, these levels were reduced to normal levels in the TY-51469-treated hamsters. CONCLUSION: TY-51469 not only prevented the progression of hepatic steatosis and fibrosis, but also ameliorated hepatic steatosis and fibrosis.
  Hepatology Research 12/2012; · 2.20 Impact Factor
• Article: Powerful vascular protection by combining cilnidipine with valsartan in stroke-prone, spontaneously hypertensive rats.

  Shinji Takai, Denan Jin, Shizuka Aritomi, Kazumi Niinuma, Mizuo Miyazaki
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  ABSTRACT: Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.Hypertension Research advance online publication, 29 November 2012; doi:10.1038/hr.2012.187.
  Hypertension Research 11/2012; · 2.58 Impact Factor
• Article: Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice.

  Tomohiro Fujisaka, Masaaki Hoshiga, Junko Hotchi, Yoshihiro Takeda, Denan Jin, Shinji Takai, Toshiaki Hanafusa, Nobukazu Ishizaka
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  ABSTRACT: BACKGROUND: Valvular aortic stenosis (AS) is not an infrequent condition in the aged population. Activation of renin-angiotensin system (RAS) is presumed to be involved in the development of AS; however, but direct evidence seems to be limited. We herein examined the effect of the administration of angiotensin II (Ang II) on the development of aortic valve thickening in apolipoprotein-E (ApoE)-deficient mice. METHODS AND RESULTS: Male ApoE-deficient mice were divided into three groups: control (saline, n = 8), mice that were administered low-dose Ang II (500 ng/kg/min, n = 11), and those with high-dose Ang II (1000 ng/kg/min, n = 11) administration for 4 weeks. Administration of high-dose, but not low-dose, Ang II significantly induced aortic valve thickening. It was found that in the aortic valve leaflets of high-dose Ang II group, integrity of endothelial cells was impaired and the number of myofibroblasts was increased. These phenomena induced by high-dose Ang II were suppressed by Ang II type 1 receptor blocker olmesartan (n = 15), but not by the dilatator, hydralazine (n = 13). Olmesartan also suppressed dilatation of aortic diameter, although it did not significantly affect the plaque area, in the abdominal aorta in ApoE-deficient mice. CONCLUSION: Administration of Ang II to genetically hyperlipidemic mice induced aortic valve thickening by a pressor-independent mechanism. Role of RAS activation in the development of AS in dyslipidemic patients should further be investigated.
  Atherosclerosis 11/2012; · 3.79 Impact Factor