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. 2006 Feb 21;47(4):827-34.
doi: 10.1016/j.jacc.2005.10.041. Epub 2006 Jan 26.

Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation

Ali J Marian  1 , Vinitha Senthil, Suet N Chen, Raffaella Lombardi
Affiliations

Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation

Ali J Marian et al. J Am Coll Cardiol. .

Abstract

Objectives: The objective was to determine the effects of antioxidant N-acetylcysteine (NAC) on reversal and attenuation of established interstitial fibrosis in the cardiac troponin T (cTnT) mouse model of human hypertrophic cardiomyopathy (HCM) mutation.

Background: Interstitial fibrosis is a characteristic pathological feature of HCM and a risk factor for sudden cardiac death. The cTnT-Q92 transgenic mice, generated by cardiac-restricted expression of human HCM mutation, show a two- to four-fold increase in interstitial fibrosis.

Methods: We randomized the cTnT-Q92 mice to treatment with a placebo or NAC (250, 500, or 1,000 mg/kg/day) and included non-transgenic mice as controls (N = 5 to 13 per group). We performed echocardiography before and 24 weeks after therapy, followed by histologic and molecular characterization.

Results: There were no significant differences in the baseline characteristics of the groups. Treatment with NAC reduced myocardial concentrations of malondialdehyde and 4-hydroxy-2(E)-nonenal, markers of oxidative stress, by 40%. Collagen volume fractions comprised 1.94 +/- 0.76% of the myocardium in non-transgenic, 6.2 +/- 1.65% in the placebo, and 1.56 +/- 0.98% in the NAC (1,000 mg/kg/day) groups (p < 0.001). Expression levels of Col1a1 and Col1a2 were also reduced significantly, as were levels of phosphorylated but not total p44/42, p38, and c-Jun NH2-terminal kinase. Levels of oxidized mitochondrial and nuclear DNA were not significantly different.

Conclusions: Treatment with NAC reduced myocardial oxidative stress, stress-responsive signaling kinases, and fibrosis in a mouse model of HCM. The potential beneficial effects of NAC in reversal of cardiac phenotype in human HCM, the most common cause of sudden cardiac death in the young, merits investigation.

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Figures

Figure 1
Figure 1
Plasma and myocardial levels of lipid peroxides. Myocardial (A) and plasma (B) levels of malondialdehyde (MDA) and 4-hydroxyalkenals (HAE) are depicted in non-transgenic (NTG) and cardiac troponin T-Q92 (cTnT-Q92) transgenic mice treated with placebo or with N-acetylcysteine (NAC). *p < 0.05 for pairwise comparisons.
Figure 2
Figure 2
Effect of NAC on CVF. Panels in 2A show representative high-magnification microscopic fields (×400) in non-transgenic (NTG), cTnT-Q92 mice treated with placebo and cTnT-Q92 mice treated with NAC. (B) Quantitative values in the three groups. *p < 0.05 for pairwise comparisons.
Figure 3
Figure 3
Expression levels of procollagen genes. Relative expression levels, corrected for the levels in NTG mice, are depicted for Col1a1, Col1a2, and Col3a1 procollagen genes.
Figure 4
Figure 4
Oxidized nuclear and mitochondrial DNA levels. (A) mtDNA isolated and digested with BamH1 restriction enzyme, which results in two bands of approximately 8 and 9 kbp, indicating the purity of the isolated mtDNA. (B) Immuno-slot blot of mtDNA (upper blot) and the corresponding ethidium bromide stained blot (lower blot) in three mice in each of the experimental groups. (C) Immuno-slot blot (upper blot) of nuclear DNA and ethidium bromide stained blot (lower blot) in three mice per experimental group.
Figure 5
Figure 5
Expression levels of selected signaling kinases. (A) Immunoblots showing expression levels of phosphorylated and total p44/42, p38, and JNK. (B, C, and D) Quantitative analysis of the relative levels of phosphorylated p44/42, p38, and JNK, respectively, all normalized to levels in the corresponding NTG group, in the experimental groups. The sum of density of 44 and 42 kDa bands were used to quantify levels of p44/42. Similarly, the sum density of 46 and 54 kDa bands were used for quantification of JNK. *p < 0.05 for pairwise comparisons.
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