Abstract
In this study, we investigated the effect of a specific chymase inhibitor, NK3201, in the progression of abdominal aortic aneurysm in a dog experimental model. Abdominal aortic aneurysms were induced in dogs by injecting elastase into the abdominal aorta. NK3201 (1 mg/kg per day, p.o.) or a placebo was started 3 days before elastase injection and continued for 8 weeks after the injection. On abdominal ultrasound, the aortic diameter was seen to gradually expand in the placebo-treated group, but not in the NK3201-treated group. Eight weeks after elastase injection, the ratio of the medial area to the total area in the placebo-treated group was significantly smaller than that in the normal group, but it was significantly larger than that in the NK3201-treated group. In addition to chymase activity, angiotensin II–forming and matrix metalloproteinase-9 activities were significantly higher in the placebo-treated group than in the normal group; in the NK3201-treated group, all of these activities were significantly decreased. On immunohistochemical analyses, there was a significantly greater number of chymase-positive cells in the placebo-treated group than in the normal group, but the number was significantly smaller in the NK3201-treated group than in the placebo-treated group. Thus, chymase inhibition may become a useful strategy for preventing abdominal aortic aneurysms.
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Thompson RW, Holmes DR, Mertens RA, et al: Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages. J Clin Invest 1995; 96: 318–326.
Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT : Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1995; 15: 1145–1151.
McMillan WD, Tamarina NA, Cipollone M, Johnson DA, Parker MA, Pearce WH : Size matters: the relationship between MMP-9 expression and aortic diameter. Circulation 1997; 96: 2228–2232.
Fang KC, Raymond WW, Blount JL, Caughey GH : Dog mast cell α-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain. J Biol Chem 1997; 272: 25628–25635.
Pyo R, Lee JK, Shipley JM, et al: Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 2000; 105: 1641–1649.
Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT : Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002; 110: 625–632.
Urata H, Kinoshita A, Misono K, Bumpus FM, Husain A : Identification of a highly specific chymase as the major angiotensin II–forming enzyme in the human heart. J Biol Chem 1990; 265: 22348–22357.
Takai S, Shiota N, Sakaguchi M, Muraguchi H, Matsumura E, Miyazaki M : Characterization of chymase from human vascular tissues. Clin Chim Acta 1997; 265: 13–20.
Caughey GH, Raymond WW, Wolters PJ : Angiotensin II generation by mast cell α- and β-chymases. Biochim Biophys Acta 2000; 1480: 245–257.
Nishimoto M, Takai S, Fukumoto H, et al: Increased local angiotensin II formation in aneurysmal aorta. Life Sci 2002; 71: 2195–2205.
Tsunemi K, Takai S, Nishimoto M, et al: Possible roles of angiotensin II–forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta. Hypertens Res 2002; 25: 817–822.
Daugherty A, Manning MW, Cassis LA : Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E–deficient mice. J Clin Invest 2000; 105: 1605–1612.
Ejiri J, Inoue N, Tsukube T, et al: Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res 2003; 59: 988–996.
Tsunemi K, Takai S, Nishimoto M, et al: A specific chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2-heptyl]acetamide (NK3201), suppresses development of abdominal aortic aneurysm in hamsters. J Pharmacol Exp Ther 2004; 309: 879–883.
Takai S, Miyazaki M : Application of a chymase inhibitor, NK3201, for prevention of vascular proliferation. Cardiovasc Drug Rev 2003; 21: 185–198.
Cecconi M, Manfrin M, Moraca A, et al: Aortic dimensions in patients with bicuspid aortic valve without significant valve dysfunction. Am J Cardiol 2005; 95: 292–294.
Nishimoto M, Takai S, Kim S, et al: Significance of chymase-dependent angiotensin II–forming pathway in the development of vascular proliferation. Circulation 2001; 104: 1274–1279.
Jin D, Ueda H, Takai S, et al: Effect of chymase inhibition on the arteriovenous fistula stenosis in dogs. J Am Soc Nephrol 2005; 16: 1024–1034.
Todd MB, Waldron JA, Jennings TA, et al: Loss of myeloid differentiation antigens precedes blastic transformation in chronic myelogenous leukemia. Blood 1987; 70: 122–131.
Kirimura K, Takai S, Jin D, et al: Role of chymase-dependent angiotensin II formation in regulating blood pressure in spontaneously hypertensive rats. Hypertens Res 2005; 28: 457–464.
Jin D, Takai S, Sakaguchi M, Okamoto Y, Muramatsu M, Miyazaki M : An antiarrhythmic effect of a chymase inhibitor after myocardial infarction. J Pharmacol Exp Ther 2004; 309: 490–497.
Kanemitsu H, Takai S, Tsuneyoshi H, et al: Chymase inhibition prevents cardiac fibrosis and dysfunction after myocardial infarction in rats. Hypertens Res 2006; 29: 57–64.
Tchougounova E, Lundequist A, Fajardo I, Winberg JO, Abrink M, Pejler G : A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 2005; 280: 9291–9296.
Vine N, Powell JT : Metalloproteinases in degenerative aortic disease. Clin Sci 1991; 81: 233–239.
Knox JB, Sukhova GK, Whittemore AD, Libby P : Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation 1997; 95: 205–212.
Longley BJ, Tyrrell L, Ma Y, et al: Chymase cleavage of stem cell factor yields a bioactive, soluble product. Proc Natl Acad Sci U S A 1997; 94: 9017–9021.
Takai S, Jin D, Sakaguchi M, et al: A novel chymase inhibitor, 4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl)3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), suppressed cardiac fibrosis in cardiomyopathic hamsters. J Pharmacol Exp Ther 2003; 305: 17–23.
Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T : Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J 1995; 9: 899–909.
Hernandez-Presa M, Bustos C, Ortego M, et al: Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-κB activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 1997; 95: 1532–1541.
Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM : Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res 1998; 83: 952–959.
Mabuchi T, Kitagawa K, Ohtsuki T, et al: Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 2000; 31: 1735–1743.
Hilgers KF, Hartner A, Porst M, et al: Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int 2000; 58: 2408–2419.
Fontaine V, Jacob MP, Houard X, et al: Involvement of the mural thrombus as a site of protease release and activation in human aortic aneurysms. Am J Pathol 2002; 161: 1701–1710.
Senior RM, Griffin GL, Mecham RP : Chemotactic activity of elastin-derived peptides. J Clin Invest 1980; 66: 859–862.
Hance KA, Tataria M, Ziporin SJ, Lee JK, Thompson RW : Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor. J Vasc Surg 2002; 35: 254–261.
Anidjar S, Dobrin PB, Eichorst M, Graham GP, Chejfec G : Correlation of inflammatory infiltrate with the enlargement of experimental aortic aneurysms. J Vasc Surg 1992; 16: 139–147.
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Furubayashi, K., Takai, S., Jin, D. et al. The Significance of Chymase in the Progression of Abdominal Aortic Aneurysms in Dogs. Hypertens Res 30, 349–357 (2007). https://doi.org/10.1291/hypres.30.349
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DOI: https://doi.org/10.1291/hypres.30.349
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