title: Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for angiotensin II type 1 receptor blocker treatment.
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 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.
authors.affiliation: Department of Cardiovascular Research Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. xianwu@med.nagoya-u.ac.jp
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Hideo
authors.initials: H
authors.lastname: Izawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Takao
authors.initials: T
authors.lastname: Nishizawa
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Weon
authors.initials: W
authors.lastname: Kim
authors.forename: Kohji
authors.initials: K
authors.lastname: Sato
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013481:Superoxides; D012965:Sodium Chloride; C437965:olmesartan; D019255:NADPH Oxidases; D002403:Cathepsins; D007930:Leucine; C108192:aloxistatin