Published online before print June 26, 2008

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(American Journal of Pathology. 2008;173:358-369.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071126

Superoxide-Dependent Cathepsin Activation Is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotensin II Type 1 Receptor Blocker Treatment

Xian Wu Cheng^*, 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^* and Mitsuhiro Yokota^||

From the Department of Cardiovascular Research Medicine,^* Nagoya University School of Medicine, Nagoya, Japan; the Department of Cardiology, Yan Bian University Hospital, Yanji, China; the Departments of Cardiology and Geriatrics, Nagoya University Graduate School of Medicine; the Department of Anatomy and Neuroscience,^¶ Hamamatsu University School of Medicine, Hamamatsu, Japan; the Department of Pharmacology and Genome Science,|| Aichigakuin University School of Dentistry, Aichigakuin, Japan; the Department of Medical Technology,^** Nagoya University School of Health Sciences, Nagoya, Japan; and the Department of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

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 up-regulation 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.