Eur J Cardiothorac Surg 2009;35:554-555. doi:10.1016/j.ejcts.2008.11.022
Copyright © 2009, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Reply to Agkul
Hideo Kanemitsua,
Shinji Takaib,*,
Mizuo Miyazakib,
Masashi Komedaa
a Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
b Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan
Received 18 November 2008;
accepted 19 November 2008.
* Corresponding author. Address: Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. Tel.: +81 72 684 7292; fax: +81 72 684 6518. (Email: pha010{at}art.osaka-med.ac.jp).
Key Words: Chymase • Angiotensin II • Transforming-growth factor (TGF)-β • Left ventricular repair (LVR) • Myocardial fibrosis
We recognize the significance of mast cell function. The point raised by Akgul is important, but it is very difficult to determine whether chymase inhibition or mast cell inhibition is more useful for prevention of fibrosis [1]. This is because chymase has many functions including the production of angiotensin II, activation of transforming-growth factor (TGF)-β and attraction of mast cells [2]. Like angiotensin II, TGF-β plays a crucial role in the acceleration of cardiac fibrosis, and blockade of either angiotensin II or TGF-β has inhibited fibrosis in cardiac tissues. In patients with liver cirrhosis, the augmentation of chymase-positive cells was accelerated along with that of angiotensin II-positive cells by the progression of fibrosis, and there were significant correlations between the number of chymase-positive cells and the number of angiotensin II-positive cells, between the number of chymase-positive cells and the degree of fibrosis, and between the number of angiotensin II-positive cells and the degree of fibrosis [3]. Chymase significantly increases the proliferation of cultured human dermal fibroblasts and this increased cellular proliferation can be completely suppressed by a chymase inhibitor, but not by an angiotensin II receptor blocker [2]. On the other hand, in a mast cell-deficient model, cardiac fibrosis is attenuated, suggesting the significance of mast cells in the fibrosis [4]. In cardiomyopathic hamsters, chymase inhibition resulted in attenuation of cardiac fibrosis along with reduction of mast cell numbers in cardiac tissues [2]. Chymase is known to play an important role in the accumulation of mast cells by activating stem cell factor [5]. Therefore, attenuation of mast cell numbers in cardiac tissues may be involved in the mechanism by which chymase inhibitors prevent cardiac fibrosis in vivo. Thus chymase may be involved in cardiac fibrosis through various enzymatic functions, and in other words chymase inhibition may contribute to the attenuation of cardiac fibrosis by mechanisms that are multiple rather than simple.
References
- Akgul A. Can cardiac fibrosis be prevented? Mast cell inhibition versus anti-chymase activity. Eur J Cardiothorac Surg 2009;35:553-554.[Free Full Text]
- Takai S, Jin D, Muramatsu M, Okamoto Y, Miyazaki M. Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis. Eur J Pharmacol 2004;501:1-8.[CrossRef][Medline]
- Komeda K, Jin D, Takai S, Hayashi M, Takeshita A, Shibayama Y, Tanigawa N, Miyazaki M. Significance of chymase-dependent angiotensin II formation in the progression of human liver fibrosis. Hepatol Res 2008;38:501-510.[CrossRef][Medline]
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- Longley BJ, Tyrrell L, Ma Y, Williams DA, Halaban R, Langley K, Lu HS, Schechter NM. Chymase cleavage of stem cell factor yields a bioactive, soluble product. Proc Natl Acad Sci U S A 1997;94:9017-9021.[Abstract/Free Full Text]
