title: N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.
abstract: Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidantN-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice (n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 (MST-1;n = 18) to administerN-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks. At the end of this period, cardiac remodeling and function was assessed via echocardiography. Fibrosis, oxidative stress, and expression of collagen types I andIIIwere quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, inMST-1 compared to wild type (P ≤ 0.001). InMST-1 mice administeredN-acetylcysteine, perivascular and interstitial fibrosis were 40% and 57% less, respectively, compared to those treated with saline (P ≤ 0. 03). Cardiac oxidative stress was 119% greater inMST-1 than in wild type (P < 0.001) andN-acetylcysteine attenuated oxidative stress inMST-1 by 42% (P = 0.005). These data indicate thatN-acetylcysteine can blunt cardiac fibrosis and related remodeling in the setting of heart failure potentially by reducing oxidative stress. This study provides the basis to investigate the role ofN-acetylcysteine in chronic heart failure.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Central Clinical School, Monash University, Melbourne, Australia beverly.giam@bakeridi.edu.au.
authors.forename: Beverly
authors.initials: B
authors.lastname: Giam
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Department of Biochemistry, Monash University, Melbourne, Australia.
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Kuruppu
authors.affiliation: Department of Biochemistry, Monash University, Melbourne, Australia.
authors.forename: A Ian
authors.initials: AI
authors.lastname: Smith
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: Horlock
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Niwanthi W
authors.initials: NW
authors.lastname: Rajapakse
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D024042:Collagen Type I; D024061:Collagen Type III; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine
keywords: Fibrosis; N‐acetylcysteine; heart failure; oxidative stress