Cardiovascular Drugs and Therapy

, Volume 27, Issue 2, pp 139–143 | Cite as

Chymase Inhibition and Cardiovascular Protection

  • Hideaki Tojo
  • Hidenori UrataEmail author


Human chymase, an angiotensin II-forming chymotrypsin-like serine proteinase, posses various biological actions mediating through local angiotensin II formation in the tissue level of many cardiovascular organs. Our previous experimental data have shown that chymase inhibitor increased a survival rate of the hamster post-myocardial infarction model with concomitant improvements of the cardiac function and hypertrophy, decreased hamster aortic atherosclerotic lesion induced by a high fat diet and improved hamster diabetic nephropathy decreasing the proteinuria and increased renal antiotensin II levels. Although chymase inhibitor has not yet been applied for clinical use, clinical cardiovascular diseases above mentioned appear to be the target of chymase inhibitor. The related basal and clinical circumstances are discussed in this review article for chymase inhibitor.


angiotensin II serine proteinase local renin-angiotensin system 


  1. 1.
    Dzau VJ. Molecular and physiological aspects of tissue renin-angiotensin system: emphasis on cardiovascular control. J Hypertens. 1988;6(supplement):S7–12.Google Scholar
  2. 2.
    Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation. 1988;77:I4–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Nishiyama A, Seth DM, Navar LG. Renal interstitial fluid angiotensin i and angiotensin ii concentrations during local angiotensin-converting enzyme inhibition. J Am Soc Nephrol. 2002;13:2207–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Urata H, Nishimura H, Ganten D. Chymase-dependent angiotensin ii forming systems in humans. Am J Hypertens. 1996;9:277–84.PubMedCrossRefGoogle Scholar
  5. 5.
    Urata H, Boehm KD, Philip A, Kinoshita A, Gabrovsek J, Bumpus FM, et al. Cellular localization and regional distribution of an angiotensin ii-forming chymase in the heart. J Clin Invest. 1993;91:1269–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Li M, Liu K, Michalicek J, Angus JA, Hunt JE, Dell’Italia LJ, et al. Involvement of chymase-mediated angiotensin ii generation in blood pressure regulation. J Clin Invest. 2004;114:112–20.PubMedGoogle Scholar
  7. 7.
    Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.PubMedCrossRefGoogle Scholar
  8. 8.
    Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, et al. Valsartan in Acute Myocardial Infarction Trial I. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.PubMedCrossRefGoogle Scholar
  9. 9.
    Adachi Y, Saito Y, Kishimoto I, Harada M, Kuwahara K, Takahashi N, et al. Angiotensin ii type 2 receptor deficiency exacerbates heart failure and reduces survival after acute myocardial infarction in mice. Circulation. 2003;107:2406–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Iwai M, Liu HW, Chen R, Ide A, Okamoto S, Hata R, et al. Possible inhibition of focal cerebral ischemia by angiotensin ii type 2 receptor stimulation. Circulation. 2004;110:843–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M, et al. Increased chymase-dependent angiotensin ii formation in human atherosclerotic aorta. Hypertension. 1999;33:1399–405.PubMedCrossRefGoogle Scholar
  14. 14.
    Ihara M, Urata H, Shirai K, Ideishi M, Hoshino F, Suzumiya J, et al. High cardiac angiotensin-ii-forming activity in infarcted and non-infarcted human myocardium. Cardiology. 2000;94:247–53.PubMedCrossRefGoogle Scholar
  15. 15.
    Uehara Y, Urata H, Sasaguri M, Ideishi M, Sakata N, Tashiro T, et al. Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia. Hypertension. 2000;35:55–60.PubMedCrossRefGoogle Scholar
  16. 16.
    Murakami K, Uehara Y, Abe S, Inoue Y, Ideishi M, Saku K, et al. Positive correlation between chymase-like angiotensin ii-forming activity in mononuclear cells and serum cholesterol level. J Cardiol. 2007;50:291–8.PubMedGoogle Scholar
  17. 17.
    Okamura K, Inoue Y, Uehara Y, Maruyama S, Sumi S, Furuyama S, et al. Chymase dependent angiotensin ii-forming activity in the circulating mononuclear leukocyte increases post acute myocardial infarction the 73rd annual scientific meeting of the japanese circulation society. Circ J. 2009;73:490.CrossRefGoogle Scholar
  18. 18.
    Hoshino F, Urata H, Inoue Y, Saito Y, Yahiro E, Ideishi M, et al. Chymase inhibitor improves survival in hamsters with myocardial infarction. J Cardiovasc Pharmacol. 2003;41 Suppl 1:S11–8.PubMedGoogle Scholar
  19. 19.
    Wei CC, Hase N, Inoue Y, Bradley EW, Yahiro E, Li M, et al. Mast cell chymase limits the cardiac efficacy of ang i-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2011;120:1229–39.CrossRefGoogle Scholar
  20. 20.
    Shiota N, Jin D, Takai S, Kawamura T, Koyama M, Nakamura N, et al. Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension. FEBS Lett. 1997;406:301–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Uehara Y, Urata H, Ideishi M, Arakawa K, Saku K. Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta. Cardiovasc Res. 2002;55:870–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Maeda Y, Inoguchi T, Takei R, Sawada F, Sasaki S, Fujii M, et al. Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters. Am J Physiol. 2010;299:F1328–38.Google Scholar
  23. 23.
    Chandrasekharan UM, Sanker S, Glynias MJ, Karnik SS, Husain A. Angiotensin ii-forming activity in a reconstructed ancestral chymase. Science. 1996;271:502–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Akasu M, Urata H, Kinoshita A, Sasaguri M, Ideishi M, Arakawa K. Differences in tissue angiotensin ii-forming pathways by species and organs in vitro. Hypertension. 1998;32:514–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Wei CC, Hase N, Inoue Y, Bradley EW, Yahiro E, Li M, et al. Mast cell chymase limits the cardiac efficacy of ang i-converting enzyme inhibitor therapy in rodents. J Clin Invest. 2010;120:1229–39.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cardiovascular DiseasesFukuoka University Chikushi HospitalChikushino-cityJapan

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