title: Mechanisms with clinical implications for atrial fibrillation-associated remodeling: cathepsin K expression, regulation, and therapeutic target and biomarker.
abstract: 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.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Fujita
authors.forename: Xian W
authors.initials: XW
authors.lastname: Cheng
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Inden
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Aiko
authors.initials: A
authors.lastname: Inoue
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.forename: Seifuku
authors.initials: S
authors.lastname: Kyo
authors.forename: Noriko
authors.initials: N
authors.lastname: Taguchi
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001281:Atrial Fibrillation / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000517:prevention & control; D015415:Biomarkers / Q000097:blood; D002304:Cardiac Pacing, Artificial; D016022:Case-Control Studies; D056657:Cathepsin K / Q000097:blood*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006325:Heart Atria / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D010748:Phosphopeptides / Q000097:blood; D010766:Phosphorylation; D011347:Procollagen / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; C062121:N-propeptide type I collagen; D010748:Phosphopeptides; D011347:Procollagen; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; C534130:CTSK protein, human; D056657:Cathepsin K
keywords: angiotensin type 1 receptor; atrial fibrillation; cathepsin K; extracellular matrix; mitogen‐activated protein kinase