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Mizuo Miyazaki - One of the best experts on this subject based on the ideXlab platform.
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Targets of Chymase inhibitors.
Expert opinion on therapeutic targets, 2011Co-Authors: Shinji Takai, Denan Jin, Mizuo MiyazakiAbstract:Introduction: Chymase converts angiotensin I to angiotensin II and it can also convert precursors of TGF-β and MMP-9 to their active forms. Therefore, diseases related to angiotensin II TGF-β, and MMP-9 could potentially be treated with Chymase inhibitors. Areas covered: This review discusses the appropriate targets and safety of Chymase inhibitors. Six diseases with notable mortality or morbidity as targets of Chymase inhibitors are focused on; abdominal aortic aneurysms (AAAs), nephropathy and retinopathy, cardiomyopathy, nonalcoholic steatohepatitis (NASH), organ fibrosis and intestinal diseases. Expert opinion: If Chymase inhibition proves to be a useful strategy for the attenuation of angiotensin II, TGF-β and MMP-9 in vivo, the application of Chymase inhibitors is likely to become widespread in various diseases in the clinical setting. Chymase inhibitors are anticipated not to interfere with the homeostasis of resting tissues, that is, those not affected by injury or inflammation.
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Chymase as an important target for preventing complications of metabolic syndrome.
Current medicinal chemistry, 2010Co-Authors: Shinji Takai, Denan Jin, Mizuo MiyazakiAbstract:Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and Chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, Chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of Chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of Chymase-positive cells was observed, and Chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, Chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by Chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by Chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by Chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, Chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of Chymase as a target to prevent complications of metabolic syndrome.
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Pathological roles of angiotensin II produced by mast cell Chymase and the effects of Chymase inhibition in animal models.
Pharmacology & therapeutics, 2006Co-Authors: Mizuo Miyazaki, Shinji Takai, Denan Jin, Michiko MuramatsuAbstract:The discovery of a new angiotensin II (Ang II) pathway generated by mast cell Chymase has highlighted new biological functions for Ang II that is not related to the classic renin-angiotensin system (RAS). The conversion of Ang I to II occurs not only via the plasma angiotensin converting enzyme (ACE) or tissue ACE but also via Chymase produced in the mast cells of humans, monkeys, dogs, and hamsters. The conversion by Chymase has been especially found in morbid tissues following the migration of mast cells. The newly discovered functions of Chymase are discussed in this review. During the vascular narrowing that occurs after vein grafting or balloon injury in dogs, Chymase activity and Ang II concentrations along with intimal proliferation are significantly increased and Chymase inhibitors completely suppressed these increase, though ACE inhibitors are ineffective. Similar results have also been confirmed in the dog arteriovenous fistula stenosis model. In both human and animal aneurysmal aortas, Chymase activity is significantly increased, and Chymase inhibitor has been shown to prevent the development of aneurysms in dogs. Chymase is activated in diseased hearts, and Chymase inhibitors reduce both the mortality rates after acute myocardial infarction and the cardiac fibrosis that leads to the development of cardiomyopathy in hamsters. Chymase is also a pro-angiogenic factor, since the injection of Chymase strongly facilitates angiogenesis in hamsters. We propose that Chymase inhibitors are effective in the prevention of multiple cardiovascular disorders, especially at the local event level without any effect on the systemic blood pressure.
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Expression of Chymase-positive cells in gastric cancer and its correlation with the angiogenesis.
Journal of surgical oncology, 2006Co-Authors: Keisaku Kondo, Shinji Takai, Yukiko Okamoto, Michiko Muramatsu, Denan Jin, Nobuhiko Tanigawa, Mizuo MiyazakiAbstract:Background and Objectives Chymase is expressed in mast cells and induces angiogenesis via activation of angiotensin II and matrix metalloproteinase-9. However, it has been unclear whether Chymase is involved in the pathophysiology of angiogenesis in gastric cancer. To clarify the contribution of Chymase to angiogenesis in gastric cancer, we assessed the relationship between Chymase-positive cells and tumor angiogenesis. Methods We evaluated Chymase-positive cells and microvessels using anti-human Chymase and anti-CD34 antibodies in 168 cases of gastric cancer, respectively. Results Chymase-positive cells in gastric tumor region were significantly higher than the cells in normal region. The number of Chymase-positive cells in the undifferentiated type of gastric tumor region was significantly higher than the one in the differentiated type. Specimens from patients with advanced histological stages of disease had more Chymase-positive cells than those with early-stage disease. There was a significant positive correlation between Chymase-positive cells and microvessels in gastric cancer specimens. Postoperative survival curves revealed that patients with a high number of Chymase-positive cells had a poor prognosis. Conclusions These results suggest that accumulation of Chymase-positive cells in gastric cancer may lead to an increase of tumor angiogenesis, and may contribute to tumor growth and progression. J. Surg. Oncol. 2006;93:36–42. © 2005 Wiley-Liss, Inc.
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Effect of Chymase on intraocular pressure in rabbits.
European journal of pharmacology, 2005Co-Authors: Takashi Konno, Shinji Takai, Akihiko Nagai, Midori Maruichi, Hidehiro Oku, Tetsuya Sugiyama, Takehiro Uchibori, Kentaro Kogi, Tsunehiko Ikeda, Mizuo MiyazakiAbstract:Chymase is a chymotrypsin-like serine protease that is stored exclusively in the secretory granules of mast cells and converts big endothelins to endothelin-1 (1-31). The aim of this study was to evaluate the effect of Chymase on intraocular pressure in rabbits. Chymase injection (3 and 10 mU) resulted in a trend toward increased intraocular pressure and a significant increase in intraocular pressure at a dose of 10 mU compared with the control. A specific Chymase inhibitor, Suc-Val-Pro-Phe(P)(OPh)(2), attenuated the ocular hypertension induced by Chymase. Endothelin-1 (1-31) also caused ocular hypertension, which was inhibited by a selective endothelin ET(A) receptor antagonist, cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123). Moreover, Chymase-induced ocular hypertension was inhibited by BQ-123. These results suggest that Chymase influences the regulation of intraocular pressure, and it is likely that the formation of endothelin-1 (1-31) and subsequent activation of endothelin ET(A) receptors are involved in the development of ocular hypertension induced by Chymase.
Shinji Takai - One of the best experts on this subject based on the ideXlab platform.
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Chymase inhibition retards albuminuria in type 2 diabetes.
Physiological reports, 2019Co-Authors: Benjamin J. Bivona, Shinji Takai, Dale M. Seth, Ryousuke Satou, Lisa M. Harrison-bernardAbstract:Chymase released from mast cells produces pro-fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic Chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a Chymase-specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of Chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle-treated diabetic mice (645 ± 108 microg/d). UNGAL V was not different at baseline between diabetic mice that would receive the Chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle-treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with Chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by Chymase inhibitor treatment. In summary, chronic Chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal Chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease.
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Comparison of a Chymase inhibitor and hyaluronic acid/carboxymethylcellulose (Seprafilm) in a novel peritoneal adhesion model in rats
2019Co-Authors: Maiko Ozeki, Shinji Takai, Denan Jin, Yuta Miyaoka, Shinsuke Masubuchi, Fumitoshi Hirokawa, Michihiro Hayashi, Kazuhisa UchiyamaAbstract:Adhesion formation that occurred after alkali-induced injury of the cecum was used as a novel adhesion model in rats, and it was compared with that of a common adhesion model after abrading the cecum. Using the novel adhesion model, inhibition of adhesion formation by a Chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, and by sodium hyaluronate/carboxymethylcellulose (Seprafilm) was evaluated, and their mechanisms were assessed. The degree of adhesion formation was more severe and more stable in the alkali-induced injury model than in the abrasion-induced injury model. Both the Chymase inhibitor and Seprafilm showed significant attenuation of the degree of adhesion 14 days after alkali-induced injury. Chymase activity in the cecum was significantly increased after alkali-induced injury, but it was significantly attenuated by the Chymase inhibitor and Seprafilm. Myeloperoxidase and transforming-growth factor (TGF)-β levels were significantly increased after alkali-induced injury, but they were attenuated by both the Chymase inhibitor and Seprafilm. At the level of the adhesions, the numbers of both Chymase-positive cells and TGF-β-positive cells were significantly increased, but their numbers were reduced by the Chymase inhibitor and Seprafilm. In conclusion, a Chymase inhibitor attenuated the degree of adhesions to the same degree as Seprafilm in a novel peritoneal adhesion model that was more severe and more stable than the common adhesion model, and not only the Chymase inhibitor, but also Seprafilm reduced the Chymase increase at the adhesions.
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Chymase Inhibitor as a Novel Therapeutic Agent for Non-alcoholic Steatohepatitis
Frontiers in pharmacology, 2018Co-Authors: Shinji Takai, Denan JinAbstract:Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease Chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented Chymase has been observed in the liver. In histological analysis, Chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis. Chymase inhibitor also attenuated the augmentation of angiotensin II, matrix metalloproteinase-9, and transforming growth factor-β observed in the liver of NASH. Oxidative stress, inflammatory markers, and collagen were attenuated by Chymase inhibition. Moreover, Chymase inhibitor showed a mitigating effect on established NASH, and survival rates were significantly increased by treatment with Chymase inhibitor. In this review, we propose that Chymase inhibitor has potential as a novel therapy for NASH.
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Improvement of cardiovascular remodelling by Chymase inhibitor
Clinical and experimental pharmacology & physiology, 2016Co-Authors: Shinji Takai, Denan JinAbstract:Chymase has been identified as an angiotensin II-forming enzyme found in cardiovascular tissues. Angiotensin II is involved not only in the regulation of blood pressure, but also in the progression of cardiovascular remodelling. Interestingly, Chymase inhibitors prevent cardiovascular remodelling without lowering blood pressure. The reason why Chymase inhibitors do not affect blood pressure may depend on the localization of Chymase in vivo. In normal tissues, Chymase is stored in mast cell granules and has no enzymatic function; whereas, in damaged tissues, Chymase exhibits enzymatic activity immediately following its release from the granules. Chymase also activates transforming growth factor-β and matrix metalloproteinase-9, both of which are involved in cardiovascular remodelling, and their enzymatic functions are also observed only in damaged tissues. In animal models of hypertension, diabetes and hypercholesterolaemia, Chymase inhibitors improve cardiovascular remodelling without a general circulatory effect, including blood pressure. Thus, it is proposed that Chymase is a potentially important target for preventing cardiovascular diseases.
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Involvement of Chymase in allergic conjunctivitis of guinea pigs
Experimental Eye Research, 2013Co-Authors: Takeshi Nabe, Yurie Kijitani, Yuriko Kitagawa, Emi Sakano, Tomoko Ueno, Shintaro Nakao, Masanori Fujii, Masaru Sakai, Shinji TakaiAbstract:Abstract It has been reported that Chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of Chymase in allergic conjunctivitis are unclear, and whether Chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of Chymase in the pathogenesis were evaluated using a selective Chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in Chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the Chymase inhibitor. Administration of human recombinant Chymase by eye dropping (0.09 and 0.9 μg/eye) dose-dependently induced scratching behavior, which was inhibited by not only ONO-WH-236 but also ketotifen; however, Chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that Chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, Chymase could be a potential target for pharmacotherapy for allergic conjunctivitis.
Denan Jin - One of the best experts on this subject based on the ideXlab platform.
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Comparison of a Chymase inhibitor and hyaluronic acid/carboxymethylcellulose (Seprafilm) in a novel peritoneal adhesion model in rats
2019Co-Authors: Maiko Ozeki, Shinji Takai, Denan Jin, Yuta Miyaoka, Shinsuke Masubuchi, Fumitoshi Hirokawa, Michihiro Hayashi, Kazuhisa UchiyamaAbstract:Adhesion formation that occurred after alkali-induced injury of the cecum was used as a novel adhesion model in rats, and it was compared with that of a common adhesion model after abrading the cecum. Using the novel adhesion model, inhibition of adhesion formation by a Chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, and by sodium hyaluronate/carboxymethylcellulose (Seprafilm) was evaluated, and their mechanisms were assessed. The degree of adhesion formation was more severe and more stable in the alkali-induced injury model than in the abrasion-induced injury model. Both the Chymase inhibitor and Seprafilm showed significant attenuation of the degree of adhesion 14 days after alkali-induced injury. Chymase activity in the cecum was significantly increased after alkali-induced injury, but it was significantly attenuated by the Chymase inhibitor and Seprafilm. Myeloperoxidase and transforming-growth factor (TGF)-β levels were significantly increased after alkali-induced injury, but they were attenuated by both the Chymase inhibitor and Seprafilm. At the level of the adhesions, the numbers of both Chymase-positive cells and TGF-β-positive cells were significantly increased, but their numbers were reduced by the Chymase inhibitor and Seprafilm. In conclusion, a Chymase inhibitor attenuated the degree of adhesions to the same degree as Seprafilm in a novel peritoneal adhesion model that was more severe and more stable than the common adhesion model, and not only the Chymase inhibitor, but also Seprafilm reduced the Chymase increase at the adhesions.
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Chymase Inhibitor as a Novel Therapeutic Agent for Non-alcoholic Steatohepatitis
Frontiers in pharmacology, 2018Co-Authors: Shinji Takai, Denan JinAbstract:Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease Chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented Chymase has been observed in the liver. In histological analysis, Chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis. Chymase inhibitor also attenuated the augmentation of angiotensin II, matrix metalloproteinase-9, and transforming growth factor-β observed in the liver of NASH. Oxidative stress, inflammatory markers, and collagen were attenuated by Chymase inhibition. Moreover, Chymase inhibitor showed a mitigating effect on established NASH, and survival rates were significantly increased by treatment with Chymase inhibitor. In this review, we propose that Chymase inhibitor has potential as a novel therapy for NASH.
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Improvement of cardiovascular remodelling by Chymase inhibitor
Clinical and experimental pharmacology & physiology, 2016Co-Authors: Shinji Takai, Denan JinAbstract:Chymase has been identified as an angiotensin II-forming enzyme found in cardiovascular tissues. Angiotensin II is involved not only in the regulation of blood pressure, but also in the progression of cardiovascular remodelling. Interestingly, Chymase inhibitors prevent cardiovascular remodelling without lowering blood pressure. The reason why Chymase inhibitors do not affect blood pressure may depend on the localization of Chymase in vivo. In normal tissues, Chymase is stored in mast cell granules and has no enzymatic function; whereas, in damaged tissues, Chymase exhibits enzymatic activity immediately following its release from the granules. Chymase also activates transforming growth factor-β and matrix metalloproteinase-9, both of which are involved in cardiovascular remodelling, and their enzymatic functions are also observed only in damaged tissues. In animal models of hypertension, diabetes and hypercholesterolaemia, Chymase inhibitors improve cardiovascular remodelling without a general circulatory effect, including blood pressure. Thus, it is proposed that Chymase is a potentially important target for preventing cardiovascular diseases.
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Targets of Chymase inhibitors.
Expert opinion on therapeutic targets, 2011Co-Authors: Shinji Takai, Denan Jin, Mizuo MiyazakiAbstract:Introduction: Chymase converts angiotensin I to angiotensin II and it can also convert precursors of TGF-β and MMP-9 to their active forms. Therefore, diseases related to angiotensin II TGF-β, and MMP-9 could potentially be treated with Chymase inhibitors. Areas covered: This review discusses the appropriate targets and safety of Chymase inhibitors. Six diseases with notable mortality or morbidity as targets of Chymase inhibitors are focused on; abdominal aortic aneurysms (AAAs), nephropathy and retinopathy, cardiomyopathy, nonalcoholic steatohepatitis (NASH), organ fibrosis and intestinal diseases. Expert opinion: If Chymase inhibition proves to be a useful strategy for the attenuation of angiotensin II, TGF-β and MMP-9 in vivo, the application of Chymase inhibitors is likely to become widespread in various diseases in the clinical setting. Chymase inhibitors are anticipated not to interfere with the homeostasis of resting tissues, that is, those not affected by injury or inflammation.
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Chymase as an important target for preventing complications of metabolic syndrome.
Current medicinal chemistry, 2010Co-Authors: Shinji Takai, Denan Jin, Mizuo MiyazakiAbstract:Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and Chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, Chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of Chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of Chymase-positive cells was observed, and Chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, Chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by Chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by Chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by Chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, Chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of Chymase as a target to prevent complications of metabolic syndrome.
Michiko Muramatsu - One of the best experts on this subject based on the ideXlab platform.
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Pathological roles of angiotensin II produced by mast cell Chymase and the effects of Chymase inhibition in animal models.
Pharmacology & therapeutics, 2006Co-Authors: Mizuo Miyazaki, Shinji Takai, Denan Jin, Michiko MuramatsuAbstract:The discovery of a new angiotensin II (Ang II) pathway generated by mast cell Chymase has highlighted new biological functions for Ang II that is not related to the classic renin-angiotensin system (RAS). The conversion of Ang I to II occurs not only via the plasma angiotensin converting enzyme (ACE) or tissue ACE but also via Chymase produced in the mast cells of humans, monkeys, dogs, and hamsters. The conversion by Chymase has been especially found in morbid tissues following the migration of mast cells. The newly discovered functions of Chymase are discussed in this review. During the vascular narrowing that occurs after vein grafting or balloon injury in dogs, Chymase activity and Ang II concentrations along with intimal proliferation are significantly increased and Chymase inhibitors completely suppressed these increase, though ACE inhibitors are ineffective. Similar results have also been confirmed in the dog arteriovenous fistula stenosis model. In both human and animal aneurysmal aortas, Chymase activity is significantly increased, and Chymase inhibitor has been shown to prevent the development of aneurysms in dogs. Chymase is activated in diseased hearts, and Chymase inhibitors reduce both the mortality rates after acute myocardial infarction and the cardiac fibrosis that leads to the development of cardiomyopathy in hamsters. Chymase is also a pro-angiogenic factor, since the injection of Chymase strongly facilitates angiogenesis in hamsters. We propose that Chymase inhibitors are effective in the prevention of multiple cardiovascular disorders, especially at the local event level without any effect on the systemic blood pressure.
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Expression of Chymase-positive cells in gastric cancer and its correlation with the angiogenesis.
Journal of surgical oncology, 2006Co-Authors: Keisaku Kondo, Shinji Takai, Yukiko Okamoto, Michiko Muramatsu, Denan Jin, Nobuhiko Tanigawa, Mizuo MiyazakiAbstract:Background and Objectives Chymase is expressed in mast cells and induces angiogenesis via activation of angiotensin II and matrix metalloproteinase-9. However, it has been unclear whether Chymase is involved in the pathophysiology of angiogenesis in gastric cancer. To clarify the contribution of Chymase to angiogenesis in gastric cancer, we assessed the relationship between Chymase-positive cells and tumor angiogenesis. Methods We evaluated Chymase-positive cells and microvessels using anti-human Chymase and anti-CD34 antibodies in 168 cases of gastric cancer, respectively. Results Chymase-positive cells in gastric tumor region were significantly higher than the cells in normal region. The number of Chymase-positive cells in the undifferentiated type of gastric tumor region was significantly higher than the one in the differentiated type. Specimens from patients with advanced histological stages of disease had more Chymase-positive cells than those with early-stage disease. There was a significant positive correlation between Chymase-positive cells and microvessels in gastric cancer specimens. Postoperative survival curves revealed that patients with a high number of Chymase-positive cells had a poor prognosis. Conclusions These results suggest that accumulation of Chymase-positive cells in gastric cancer may lead to an increase of tumor angiogenesis, and may contribute to tumor growth and progression. J. Surg. Oncol. 2006;93:36–42. © 2005 Wiley-Liss, Inc.
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The Role of Chymase in Vascular Remodeling and Tissue Fibrosis
Current Hypertension Reviews, 2005Co-Authors: Shinji Takai, Michiko Muramatsu, Denan Jin, Mizuo MiyazakiAbstract:Chymase generates angiotensin II which plays a crucial role in vascular remodeling. In clinical studies, an angiotensin II receptor blocker was successful in preventing restenosis after percutaneous coronary intervention, but an angiotensin II-converting enzyme inhibitor was not. In dog, Chymase activity was significantly increased in vessels injured by a balloon catheter, and a Chymase inhibitor and an angiotensin II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. Chymase also activates matrix metalloproteinase-9, and their function may play an important role in development of atherosclerosis and aneurysmal aorta. In human atherosclerosis and aneurysmal aorta, Chymase activity was significantly increased. In the experimental models, Chymase activity and mRNA level were also significantly increased in atherosclerotic lesions and aneurysmal aorta, but Chymase inhibitors prevented the vascular remodeling. On the other hand, Chymase activates latent transforming growth factor-β-binding protein to transforming growth factor-β, and its function may be related in promoting tissue fibrosis. Chymase promotes activations of angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, and Chymase inhibitors may promise to prevent vascular remodeling and tissue fibrosis.
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Therapeutic applications of Chymase inhibitors in cardiovascular diseases and fibrosis.
European journal of pharmacology, 2004Co-Authors: Shinji Takai, Yukiko Okamoto, Michiko Muramatsu, Denan Jin, Mizuo MiyazakiAbstract:Chymase activates not only angiotensin I to angiotensin II but also latent transforming growth factor-beta-binding protein to transforming growth factor-beta. In dog grafted veins, Chymase activity and angiotensin II concentration along with vascular proliferation were significantly increased, while they were significantly suppressed by a Chymase inhibitor. After balloon injury in dog arteries, Chymase activity was significantly increased in the injured artery, and a Chymase inhibitor and an angiotensin AT(1) receptor antagonist were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In fibrotic models, the tissue fibrosis was reduced by Chymase inhibitors. In adhesion models, the transforming growth factor-beta concentration and adhesion formation were suppressed by Chymase inhibitors. Therefore, Chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin II formation and transforming growth factor-beta activation.
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Therapeutic applications of Chymase inhibitors in cardiovascular diseases and fibrosis.
European Journal of Pharmacology, 2004Co-Authors: Shinji Takai, Yukiko Okamoto, Michiko Muramatsu, Denan Jin, Mizuo MiyazakiAbstract:Abstract Chymase activates not only angiotensin I to angiotensin II but also latent transforming growth factor-β-binding protein to transforming growth factor-β. In dog grafted veins, Chymase activity and angiotensin II concentration along with vascular proliferation were significantly increased, while they were significantly suppressed by a Chymase inhibitor. After balloon injury in dog arteries, Chymase activity was significantly increased in the injured artery, and a Chymase inhibitor and an angiotensin AT 1 receptor antagonist were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In fibrotic models, the tissue fibrosis was reduced by Chymase inhibitors. In adhesion models, the transforming growth factor-β concentration and adhesion formation were suppressed by Chymase inhibitors. Therefore, Chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin II formation and transforming growth factor-β activation.
Ilkka T. Harvima - One of the best experts on this subject based on the ideXlab platform.
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Mast cell Chymase degrades fibrinogen and fibrin
The British journal of dermatology, 2019Co-Authors: Tiina Lipitsä, Hanna Siiskonen, Anita Naukkarinen, Ilkka T. HarvimaAbstract:Background The accumulation of immunoreactants and fibrinoid necrosis of postcapillary vessel walls are common pathological features of cutaneous immune complex vasculitis. In more advanced lesions, these immunoreactants are subject to proteolysis. Mast cell Chymase is a powerful enzyme that can degrade several substrates including the extracellular matrix. Heparin can influence the catalytic properties of Chymase. Objectives To study the effects of recombinant human (rh) Chymase on fibrinogen, coagulation and fibrinolysis, and to relate these effects to the pathogenesis of vasculitis. Methods The colocalization of Chymase and fibrin in vasculitis specimens was analysed by immunohistochemical double staining. Fibrinogen and fibrin were treated with rh-Chymase and the effects were studied in vitro by sodium dodecylsulfate polyacrylamide gel electrophoresis and a variety of clotting and fibrin gel experiments. The effects of rh-Chymase on vasculitis cryosections were analysed by direct immunofluorescence. Results Chymase-positive mast cells were associated with fibrin-positive vessels in vasculitis cryosections. Rh-Chymase degraded the alpha-, beta- and gamma-chains of fibrinogen, while heparin enhanced the degradation of the beta-chain. Rh-Chymase pretreatment of fibrinogen prolonged thrombin-induced clotting time. Fibrinogen degradation products induced by rh-Chymase increased the clotting time of human plasma. Rh-Chymase degraded fibrin gel prepared from fibrinogen or human plasma. Immunofluorescence staining positivity of fibrin in vasculitis cryosections decreased after pretreatment with rh-Chymase for 24 h, and heparin enhanced this effect. Conclusions Mast cell Chymase may constitute a previously unrecognized endogenous anticoagulant and fibrinolytic enzyme, and may be involved in the clearance of fibrin from vessel walls in aged vasculitis lesions.
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Complement C3 is expressed by mast cells in cutaneous vasculitis and is degraded by Chymase
Archives of Dermatological Research, 2016Co-Authors: Tiina Lipitsä, Anita Naukkarinen, Joel Laitala, Ilkka T. HarvimaAbstract:The complement factor C3 and Chymase released from tryptase^+, Chymase^+ mast cells may be involved in the pathogenesis of cutaneous leukocytoclastic vasculitis. To study whether mast cells contain C3 in vasculitis and whether Chymase interacts with C3, cryosections from vasculitis biopsies were double-stained histochemically for C3c in tryptase^+ mast cells, as well as for Chymase and vessel wall C3c, or they were treated with 5 µg/ml rh-Chymase for 24 h followed by immunofluorescence (IF) analysis of C3c, IgG, IgM and IgA. The effect of rh-Chymase on purified human C3, C3a and IgG was studied using SDS-PAGE electrophoresis and LAD2 mast cell cultures. The results show that 34.2 ± 17.9, 37.4 ± 15.5 and 43.4 ± 18.6 % (mean ± SD) of the mast cells express C3c immunoreactivity in the healthy skin, initial petechial (IP) and palpable purpura (PP) lesions, respectively. About 9.4–12.1 % of the Chymase^+ mast cells were in apparent contact with C3c^+ vessels in IP and PP. The treatment of cryosections with rh-Chymase decreased the IF staining of C3c, but not that of immunoglobulins. In SDS-PAGE, 1–10 µg/ml rh-Chymase degraded the alpha- and beta-chains of C3, but did not degrade IgG. Unexpectedly, the rh-Chymase treatment of C3 produced fragments that resulted in the release of tryptase and histamine from LAD2 cells. However, rh-Chymase degraded C3a and consequently inhibited C3a activity on LAD2. In conclusion, mast cells can be one source for C3 in the early and late phases of vasculitis pathogenesis. However, rh-Chymase degraded native C3, vessel wall C3c, and biologically active C3a. Therefore, Chymase may control C3-related pathology.
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Mast cell Chymase in experimentally induced psoriasis.
The Journal of dermatology, 2015Co-Authors: Mireille-maria Suttle, Ilkka T. HarvimaAbstract:Mast cell Chymase can have a pro-inflammatory or an immunosuppressive function in psoriasis, but the outcome may depend on the level of Chymase activity. Therefore, mast cells showing Chymase activity (Chyact ) and immunoreactivity (Chyprot ) were studied during the Kobner reaction (0 days, 2 h, 1 day, 3 days and 7 days) of psoriasis induced by the tape-stripping technique. Also, the effect of recombinant human Chymase (rh-Chymase) or human LAD2 mast cells (LAD2) on the (3) H-thymidine uptake of psoriatic peripheral blood mononuclear cells (PBMC) or total T cells was studied. The Chyact /Chyprot ratio tended to be higher in all time-point biopsies in the Kobner-negative (n = 10) than -positive (n = 8) group (P = 0.073), although Chymase activity decreased significantly at 2 h to 1 day only in the Kobner-negative group. rh-Chymase (0.05-0.5 μg/mL) stimulated to a varying extent PBMC in eight out of nine cultures, but in all cultures 5 μg/mL rh-Chymase turned the stimulation towards inhibition. The effect of rh-Chymase on T cells varied from stimulation to inhibition, but in 11 of 15 cultures rh-Chymase, at least at 5 μg/mL, produced a change to inhibition. In co-cultures, LAD2 inhibited PBMC in the absence of soybean trypsin inhibitor (SBTI). In the presence of SBTI, LAD2 stimulated PBMC in the majority of seven cultures. In summary, the psoriatic immunopathogenesis may be promoted at low, but controlled at high, activity status of Chymase.
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Mast cell tryptase and Chymase in the progress of cutaneous vasculitis
Archives of Dermatological Research, 2015Co-Authors: Tiina Lipitsä, Anita Naukkarinen, Ilkka T. HarvimaAbstract:In animal models of vasculitis, mast cells are essential in the pathogenesis, but their involvement in human skin vasculitis is obscure. Because tryptase and Chymase are potent serine proteinases in the secretory granules of mast cells, the purpose was to examine the number of mast cells expressing tryptase and Chymase during the progress of cutaneous vasculitis. These numbers were correlated with the appearance of immunoreactants (C3c, fibrin, IgM, IgA and IgG) in vessel walls. For this, skin biopsies were taken from the healthy-looking skin, initial petechial lesion (IP), and palpable purpura (PP) of the leg of patients with leukocytoclastic vasculitis ( n = 10). The frozen biopsies were analysed using enzyme- and immunohistochemistry and direct immunofluorescence (IF) staining. The results show that there are no marked changes in the numbers of mast cells expressing Chymase or tryptase proteins. Instead, Chymase enzyme activity decreased, but the score of α_1-antichymotrypsin staining increased, during the progress of vasculitis. The IF positivity of fibrin correlated positively with Chymase activity ( p = 0.01) and the ratio of Chymase activity to tryptase protein in IP ( p = 0.03), as well as with mast cells showing tryptase ( p = 0.03) and Chymase ( p = 0.01) proteins in PP. The IF positivity of C3c correlated with the ratio of Chymase activity to tryptase protein in IP ( p = 0.01). In conclusion, Chymase is partially inactivated in vasculitis possibly due to α_1-antichymotrypsin. Several positive correlations between Chymase and fibrin and/or C3c in IP or PP suggest that this enzyme is involved in the deposition of immunoreactants in the vessel wall.
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The increase in tryptase‐ and Chymase‐positive mast cells is associated with partial inactivation of Chymase and increase in protease inhibitors in basal cell carcinoma
Journal of the European Academy of Dermatology and Venereology : JEADV, 2007Co-Authors: Nicolae-costin Diaconu, Anita Naukkarinen, Rauno J. Harvima, Renata Kaminska, Ilkka T. HarvimaAbstract:Background In basal cell carcinoma (BCC), mast cells accumulate in the peritumoral stroma. The serine proteinases tryptase and Chymase are the major mediators in mast cell granules and they may exert their enzymatic activity in the BCC lesion by inducing matrix remodeling and epithelial cell detachment. Objective To analyse the numbers of mast cells showing tryptase enzyme activity, Chymase enzyme activity and Chymase immunoreactivity as well as the presence of Chymase inhibitors α 1 -antichymotrypsin ( α 1 -AC), α 1 -proteinase inhibitor ( α 1 -PI) and squamous cell carcinoma antigen-2 (SCCA-2) in BCC. Methods Eleven biopsies were taken from the lesion and healthy-looking skin of 10 patients with superficial spreading BCC. The frozen biopsies were analysed enzyme- and immunohistochemically, and a sequential double-staining method was applied. Results In the BCC lesion, the number of mast cells with tryptase activity and Chymase immunoreactivity was significantly increased by 2.2- to 2.3-fold. Practically all tryptase-immunopositive cells contained tryptase activity although occasional tryptase-immunopositive cells (about 1% of total) revealed no activity. However, the ratio of cells with Chymase activity to those with Chymase immunoreactivity was significantly decreased from 49 ± 19% in the healthy skin to 33 ± 19% in the BCC lesion. Instead, the percentage of mast cells displaying α 1 -AC or α 1 -PI immunoreactivity was significantly increased by 1.7-fold in the BCC lesion. SCCA-2 expression was strongly increased in the malignant BCC epithelium but mostly in the suprabasal layers. Conclusions Tryptase- and Chymase-positive mast cells (MC TC ) increased in the BCC lesion. However, Chymase is partially inactivated, possibly by the effective Chymase inhibitors α 1 -AC and α 1 -PI. SCCA-2 increased in BCC, but was localized mostly to the suprabasal layers, and thus it seems not to be crucial in inhibiting Chymase.