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N‐acetylcysteine reverses established cardiac and renal fibrosis in a mouse model of heart failure
Author(s) -
Rajapakse Niwanthi,
Giam Beverly,
Chu PoYin,
Kiriazis Helen,
Du XiaoJun,
Kaye David M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.735.4
Subject(s) - cardiac fibrosis , medicine , fibrosis , acetylcysteine , cardiac function curve , heart failure , myocardial fibrosis , saline , masson's trichrome stain , cardiomyopathy , genetically modified mouse , renal function , endocrinology , pathology , cardiology , transgene , antioxidant , biology , biochemistry , gene
Background Patients with heart failure (HF) often develop secondary renal dysfunction and fibrosis plays a major pathological role in the development of both cardiac and renal dysfunction in these patients. We aimed to determine whether the antioxidant N‐acetylcysteine (NAC) can reverse cardiac and renal fibrosis in a transgenic mouse model of HF. These mice develop cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20–like kinase 1 (MST‐1).1 Overexpression of MST‐1 in cardiomyocytes induces apoptosis1 which is relevant to human HF and we have previously demonstrated that mice with cardiac specific overexpression of MST‐1 (MST‐1 mice) develop extensive cardiac fibrosis by 13 weeks of age.2 The aim of the current study was to determine whether NAC can reverse cardiac and renal fibrosis in the setting of HF. Methods Minipumps were implanted subcutaneously in 18 week old male wild type (WT; n =6–20) and MST‐1 mice ( n =6–10) to administer NAC (40 mg/kg/day) or saline for a period of 8 weeks. At the end of this treatment period, cardiac remodelling and function was assessed via echocardiography. Fibrosis in the heart and kidney tissues was quantified using Masson Trichrome staining. Results Cardiac perivascular and interstitial fibrosis were 2‐ and 19‐fold greater, respectively, in saline treated MST‐1 mice compared to saline treated WT ( P ≤ 0.01). In NAC treated MST‐1 mice, perivascular and interstitial fibrosis were 37% and 68% less, respectively, compared to those treated with saline ( P ≤ 0.05). Fractional shortening was 61% less in saline treated MST‐1 mice compared to saline treated WT. Fractional shortening was not significantly different between NAC treated MST‐1 mice and those treated with saline. Heart weight:body weight ratio was 27% greater in saline treated MST‐1 mice compared to saline treated WT ( P < 0.05). This ratio was not significantly different between NAC treated MST‐1 mice and saline treated MST‐1 mice. Renal tubulointerstitial and glomerular fibrosis were 23‐ and 2‐fold greater, respectively, in saline treated MST‐1 mice compared to saline treated WT ( P ≤ 0.01). Of interest, renal tubulointerstitial and glomerular fibrosis were 99% and 67% less, respectively, in NAC treated MST‐1 mice compared to those treated with saline ( P ≤ 0.01). Conclusions These data indicate that NAC can reverse cardiac and renal fibrosis in the setting of HF potentially by reducing oxidative stress. Support or Funding Information This work was supported by a NHMRC (Australia) program grant.