title: Cathepsin A mediates susceptibility to atrial tachyarrhythmia and impairment of atrial emptying function in Zucker diabetic fatty rats.
abstract: Type 2 diabetes (T2D) is an independent risk factor for atrial fibrillation (AF) and stroke. The serine protease cathepsin A (CatA) is up-regulated in diabetes and plays an important role in the degradation of extracellular peptides. This study sought to delineate the role of CatA for the development of atrial remodelling under diabetic conditions.
  
  
  
  Zucker Diabetic Fatty rats (ZDF) were treated with vehicle (n = 20) or CatA-inhibitor (SAR; 50 mg/kg; n = 20), and compared with age-matched non-diabetic littermates (Ctr, n = 20). Left-atrial (LA) emptying function [magnetic resonance imaging (MRI)] and atrial electrophysiological parameters were measured before sacrifice for histological and biochemical analysis. The impact of enhanced cardiac CatA expression on atrial remodelling was determined using CatA-transgenic mice. At the age of 9.5 months, atrial tissues of ZDF rats showed increased CatA gene expression and CatA-activity, along with increased AF-susceptibility and impaired LA-emptying function. CatA-inhibition reduced CatA-activity in ZDF comparable to Ctr values and decreased LA-fibrosis formation and connexin 43 lateralization. This was associated with shorter median duration of LA-tachyarrhythmia (12.0 ± 1.7 vs. 1.2 ± 0.47 s, P < 0.01) induced by burst pacing and diminished regions of slow conduction. Cardiac MRI revealed better LA-emptying function parameters (active per cent emptying: 29 ± 1 vs. 23 ± 2%, P < 0.01) after CatA-inhibition. CatA-inhibition reduced LA bradykinin-degrading activity in ZDF. Transgenic mice overexpressing CatA demonstrated enhanced atrial fibrosis formation and increased AF-susceptibility.
  
  
  
  T2D leads to arrhythmogenic atrial remodelling in ZDF rats. CatA-inhibition reduces LA bradykinin-degrading activity in ZDF and suppresses the development of atrial structural changes and AF-promotion, implicating CatA as an important mediator for AF-substrate in T2D.
authors.affiliation: Department of Physiology, University Maastricht, Maastricht, The Netherlands Universitätsklinikum des Saarlandes, Homburg/Saar, Germany dominik.linz@gmx.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Linz
authors.affiliation: Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.affiliation: Herzzentrum Leipzig Abt. Herzchirurgie, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dhein
authors.affiliation: Sanofi Deutschland GmbH, Frankfurt, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Ruf
authors.affiliation: Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: Jan-Christian
authors.initials: JC
authors.lastname: Reil
authors.affiliation: Sanofi Deutschland GmbH, Frankfurt, Germany.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Kabiri
authors.affiliation: Sanofi Deutschland GmbH, Frankfurt, Germany.
authors.forename: Paulus
authors.initials: P
authors.lastname: Wohlfart
authors.affiliation: Department of Physiology, University Maastricht, Maastricht, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.affiliation: Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Sanofi Deutschland GmbH, Frankfurt, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Sadowski
authors.affiliation: Department of Physiology, University Maastricht, Maastricht, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
mesh_terms: D000200:Action Potentials; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D016279:Atrial Function, Left / Q000187:drug effects; D064752:Atrial Remodeling / Q000187:drug effects; D001920:Bradykinin / Q000378:metabolism; D043402:Cathepsin A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006339:Heart Rate; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011924:Rats, Zucker; D013997:Time Factors
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D011480:Protease Inhibitors; D000804:Angiotensin II; C468629:CTSA protein, human; D043402:Cathepsin A; D001920:Bradykinin
keywords: Atrial emptying function; Atrial fibrillation; Cathepsin A; Diabetes; Remodelling