N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.

Beverly Giam,Xiao-Jun Du,A Ian Smith,Helen Kiriazis,David M Kaye,Duncan Horlock,Po-Yin Chu,Sanjaya Kuruppu,Niwanthi W Rajapakse

doi:10.14814/phy2.12757

Beverly Giam, Xiao-Jun Du + Show 7 more

Open Access

https://doi.org/10.14814/phy2.12757

Copy DOI

Abstract

Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidant N‐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 administer N‐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 and III were quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, in MST‐1 compared to wild type (P ≤ 0.001). In MST‐1 mice administered N‐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 in MST‐1 than in wild type (P < 0.001) and N‐acetylcysteine attenuated oxidative stress in MST‐1 by 42% (P = 0.005). These data indicate that N‐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 of N‐acetylcysteine in chronic heart failure.

Highlights

Heart failure (HF) is increasing at a rapid rate worldwide in part due to an ageing population and high prevalence of obesity, diabetes, and hypertension
We found that cardiac perivascular and interstitial fibrosis and cardiac expression of collagen types I and III were greater in mammalian sterile 20-like kinase 1 (MST-1) mice compared to WT mice
We found that perivascular and cardiac interstitial fibrosis were less in MST-1 mice treated with NAC compared to those treated with saline vehicle

Summary

Introduction

Heart failure (HF) is increasing at a rapid rate worldwide in part due to an ageing population and high prevalence of obesity, diabetes, and hypertension. There is evidence that oxidative stress plays a role in the development of angiotensin II-dependent cardiac fibrosis in rats (Zhao et al 2008; Worou et al 2011) and mice (Li et al 2013). In this context, it is of interest to note that the presence of oxidative stress is widely documented in patients with chronic HF regardless of the underlying etiology (McMurray et al 1993; Thomson et al 2009). Therapeutic strategies which target oxidative stress have received much attention in the setting of HF (Thomson et al 2009)

Objectives

Methods

Conclusion