Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins

Tsunemi, Koutaro; Takai, Shinji; Nishimoto, Masashi; Yuda, Atsushi; Jin, Denan; Sakaguchi, Masato; Sawada, Yoshihide; Asada, Kunio; Kondo, Keiichiro; Sasaki, Satoshi; Miyazaki, Mizuo

doi:10.1067/mtc.2002.125164

Cited by 19 publications

(10 citation statements)

References 26 publications

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“…Total Ang II-forming activity, ACE, and chymase activities were measured using cardiac tissue slices according to methods described previously (Takai et al, 1998;Tsunemi et al, 2002). Plasma norepinephrine (NE), Ang II, CPK-MB, and GOT were measured by SRL Inc. (Setsu, Japan).…”

Section: Methodsmentioning

confidence: 99%

An Antiarrhythmic Effect of a Chymase Inhibitor after Myocardial Infarction

Jin

Takai²,

Sakaguchi³

et al. 2004

J Pharmacol Exp Ther

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Chymase plays an important role in the regulation of local angiotensin (Ang) II formation in the cardiac tissue. We recently found that cardiac chymase was activated significantly and survival rate markedly improved by treatment with chymase inhibitors after myocardial infarction (MI) in hamsters. However, the mechanisms for this effect have not been established. Because lethal arrhythmias are generally believed to contribute to sudden cardiac death, we assessed whether inhibition of cardiac chymase would provide an antiarrhythmic effect during the 8-h ischemic period after 2-[4-(5-fluoro-3-methylbenzo-[b]thiophen-2-yl)sulfonamide-3-methanesulfonylphenyl]oxazole-4-carboxylicacid (TY51184) (a specific chymase inhibitor, 1 mg/kg i.v.) treatment by ligation of left anterior descending coronary artery (LAD) in dogs. Effects of candesartan (an Ang II type 1 receptor antagonist, 1 mg/kg i.v.) in this model were also assessed. Total Ang II-forming activity and chymase activity in the infarcted heart were increased significantly 8 h after LAD ligation. A time-dependent elevation of Ang II in plasma was also observed. A decrease in plasma Ang II levels after TY51184 treatment occurred concomitantly with suppression of cardiac chymase activity. LAD ligation resulted in a large number of ventricular arrhythmias (VAs). TY51184 and candesartan treatments largely suppressed the appearance of VAs, and the efficacy of the two agents was similar. These findings demonstrate that chymase inhibition can provide an antiarrhythmic effect after MI, and the reduction of Ang II by TY51184 may be mainly responsible for this beneficial effect. An antiarrhythmic effect of chymase inhibitors may contribute to reductions in the mortality rate during the acute phase after MI.

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Section: Methodsmentioning

confidence: 99%

An Antiarrhythmic Effect of a Chymase Inhibitor after Myocardial Infarction

Jin

Takai²,

Sakaguchi³

et al. 2004

J Pharmacol Exp Ther

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“…Chymase activity in the grafted veins was activated in the acute phase after grafting, and chymase-dependent Ang II-forming activity was especially accelerated, suggesting that activated chymase-dependent Ang II formation may be important in the development of vascular proliferation. In fact, a single treatment with Suc-Val-Pro-Phe P (OPh) 2 into grafted veins maintained the suppression of chymase activity and vascular proliferation even 3 months after the grafting [38].…”

Section: Stenosis In Vein Graftsmentioning

confidence: 97%

Chymase Inhibitor As a Novel Therapeutic Strategy for Anti-Vascular Remodeling

Takai¹,

Jin²,

Muramatsu³

et al. 2006

Vascular Disease Prevention

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Chymase forms angiotensin II (Ang II) which plays a crucial role in vascular diseases. In dog grafted veins, chymase activity and Ang II concentration along with vascular proliferation were significantly increased, while they were completely suppressed by a chymase inhibitor. After balloon injury in dog arteries, vascular chymase activity was significantly increased, and a chymase inhibitor and an Ang II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In clinical studies, an Ang II receptor blocker was successful in preventing restenosis after percutaneous coronary intervention, but an Ang II-converting enzyme inhibitor was not. In human and animal atherosclerosis, chymase activity was significantly increased, and a chymase inhibitor prevented experimental atherosclerosis. These observations suggest chymase may promote vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase-9 which promotes aortic aneurysm and angiogenesis. In human aortic aneurysms, chymase activity was significantly higher than in the normal aortas. In a hamster aneurysm model, chymase activity was also higher in the aneurysmal aortas than in the normal aortas, whereas a chymase inhibitor significantly prevented the aortic aneurysm. Chymase also acts as a pro-angiogenic factor, because the injections of the chymase gene or of purified chymase into implanted sponges strongly facilitate angiogenesis in hamsters. The mechanism of chymase-induced angiogenesis may depend not only on Ang II formation but also on activation of matrix metalloproteinase-9. In this review, we propose chymase inhibitors as a novel therapeutic strategy for anti-vascular remodeling.

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“…Chymase activities in the grafted veins was activated at acute phase after grafting, and the angiotensin II-forming activity via chymase was especially accelerated, suggesting that the activated angiotensin II formation via chymase may be important in the development of vascular proliferation. In fact, a single treatment with Suc-Val-Pro-Phe P (OPh) 2 into grafting veins maintained the suppression of chymase activity and vascular proliferation even 3 months after the operation [56]. Recently, oral administration of chymase inhibitors, NK3201 and TY-51184, could also prevent both the chymase activity and the vascular proliferation in the grafted veins [57,58].…”

Section: Role Of Chymase In Vascular Proliferat-ion In Injured Vesselsmentioning

confidence: 97%

The Role of Chymase in Vascular Remodeling and Tissue Fibrosis

Jin¹,

Muramatsu²,

Miyazaki

2005

CHYR

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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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Lengthy suppression of vascular proliferation by a chymase inhibitor in dog grafted veins

Cited by 19 publications

References 26 publications

An Antiarrhythmic Effect of a Chymase Inhibitor after Myocardial Infarction

An Antiarrhythmic Effect of a Chymase Inhibitor after Myocardial Infarction

Chymase Inhibitor As a Novel Therapeutic Strategy for Anti-Vascular Remodeling

The Role of Chymase in Vascular Remodeling and Tissue Fibrosis

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