Mechanisms With Clinical Implications for Atrial Fibrillation-Associated Remodeling: Cathepsin K Expression, Regulation, and Therapeutic Target and Biomarker

作者：Fujita Masaya; Cheng Xian Wu^*; Inden Yasuya; Shimano Masayuki; Yoshida Naoki; Inoue Aiko; Yamamoto Toshihiko; Takeshita Kyosuke; Kyo Seifuku; Taguchi Noriko; Shi Guo Ping; Kuzuya Masafumi; Okumura Kenji; Murohara Toyoaki

来源：Journal of the American Heart Association, 2013, 2(6): e000503.

DOI：10.1161/JAHA.113.000503

• angiotensin type 1 receptor
• atrial fibrillation
• cathepsin K
• extracellular matrix
• mitogen-activated protein kinase

Background-The cysteine protease cathepsin K (CatK) has been implicated in the pathogenesis of cardiovascular disease. We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression of and therapeutic target for CatK in vivo and in vitro. %26lt;br%26gt;Methods and Results-Plasma CatK and extracellular matrix protein peptides (intact procollagen type I of N-terminal propeptide; carboxyl-terminal telopeptide of type I collagen [ICTP]) were measured in 209 consecutive patients with AF (paroxysmal AF, 146; persistent AF, 63) and 112 control subjects. In addition, the regulation of CatK expression was investigated in vivo and vitro. Patients with AF had higher plasma CatK and ICTP levels than did control subjects. Patients with persistent AF had higher levels of plasma CatK and ICTP than did patients with paroxysmal AF. CatK was correlated with ICTP concentration and left atrial diameter in all subjects. In rabbits, superoxide production, CatK activity, fibrosis, and the levels of atrial tissue angiotensin II, angiotensin type 1 receptor, gp91phox, phospho-p38 mitogen-activated protein kinase, and CatK were greater in those with tachypacing-induced AF than in controls, and these changes were reversed with angiotensin type 1 receptor antagonist. Olmesartan and mitogen-activated protein kinase inhibitor decreased the CatK expression induced by angiotensin II in rat neonatal myocytes. %26lt;br%26gt;Conclusions-These data indicated that increased plasma CatK levels are linked with the presence of AF. Angiotensin type 1 receptor antagonist appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing angiotensin type 1 receptor-p38mitogen-activated protein kinase-dependent and -independent CatK activation, thus preventing AF.

• 出版日期2013-12
• 单位延边大学