Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment

Wu Cheng Xian, Toyoaki Murohara, Masafumi Kuzuya, Hideo Izawa, Takeshi Sasaki, Koji Obata, Kohzo Nagata, Takao Nishizawa, Masakazu Kobayashi, Takashi Yamada, Weon Kim, Kohji Sato, Guo Ping Shi, Kenji Okumura, Mitsuhiro Yokota

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Abstract

The elastolytic activity of cathepsins in the myocardium is implicated in hypertensive heart failure (HF). Given that reactive oxygen species are also implicated in protease activation associated with cardiac remodeling, we examined the role of the reactive oxygen species-induced cathepsin activation system in cardiac remodeling during the development of hypertensive HF. Dahl salt-sensitive hypertensive rats maintained on a high-salt diet were treated with vehicle, the cathepsin inhibitor E64d, or the angiotensin receptor blocker olmesartan from 12 to 19 weeks of age. Cathepsin expression and activity were increased in the left ventricle of HF rats; olmesartan inhibited these effects, restored the balance between elastin and collagen in the left ventricle, and suppressed degradation of the elastic lamina of coronary arteries of HF rats. Furthermore, olmesartan inhibited upregulation of NADPH oxidase subunits and activity as well as superoxide generation. These effects of olmesartan were mimicked by E64d and were accompanied by amelioration of cardiac fibrosis. Finally, olmesartan and apocynin reduced angiotensin II-induced increases in cathepsin mRNA and protein levels in cultured rat neonatal cardiac myocytes. These data suggest that cathepsins likely trigger and promote cardiac remodeling and that blocking the angiotensin II type 1 receptor attenuates cathepsin expression and activity by inhibiting the production of superoxide by NADPH oxidase, thereby attenuating cardiac remodeling and dysfunction.

Original languageEnglish
Pages (from-to)358-369
Number of pages12
JournalAmerican Journal of Pathology
Volume173
Issue number2
DOIs
Publication statusPublished - 08-2008

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Xian, W. C., Murohara, T., Kuzuya, M., Izawa, H., Sasaki, T., Obata, K., Nagata, K., Nishizawa, T., Kobayashi, M., Yamada, T., Kim, W., Sato, K., Shi, G. P., Okumura, K., & Yokota, M. (2008). Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment. American Journal of Pathology, 173(2), 358-369. https://doi.org/10.2353/ajpath.2008.071126