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Oxidative Stress in Transgenic Mice with AZT Cardiomyopathy
Author(s) -
Cucoranu Ioan Corneliu,
Kohler James,
Hosseini Seyed,
Johnson David,
Green Elgin,
Hoying Amy,
Russ Rodney,
Fields Earl,
Wittich Bree,
He Stanley,
Jones Dean,
Lewis William
Publication year - 2008
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.22.1_supplement.466.3
Subject(s) - ventricle , oxidative stress , cardiomyopathy , thioredoxin , zidovudine , medicine , mitochondrion , genetically modified mouse , thioredoxin reductase , heart failure , endocrinology , transgene , chemistry , cardiology , virology , human immunodeficiency virus (hiv) , biochemistry , viral disease , gene
BACKGROUND CM and myocarditis occur in HIV/AIDS and symptomatic heart failure is reported in up to 5% of HIV/AIDS patients. Highly active antiretroviral therapy (HAART) significantly reduced morbidity and mortality of AIDS, but has resulted in an increase in cardiac and skeletal myopathies. The thioredoxin (TRX) system is a ubiquitous thiol oxidoreductase system that regulates cellular reduction/oxidation status in the cytoplasm (Trx1) and in mitochondria (Trx2). To identify if oxidative stress is involved in cardiomyopathy induced by the HAART component Zidovudine (AZT) two TGs were employed. One TG exhibits down‐regulated cytosolic thioredoxin in the heart (Tg‐Trx1‐DN) the second TG exhibits overexpression of mitochondrial thioredoxin (Tg‐Trx2). METHODS: TGs and WT littermates were treated with AZT (0.22 mg/day via gavage, n=7). After 35 d, left ventricle (LV) mass and left ventricle end diastolic dimension (LVEDD) were analyzed quantitatively by echocardiography (ECHO; 2D and M mode). RESULTS: In WT, AZT significantly increased LV mass with a mild increase of LVEDD. Both treated and untreated Trx2 overexpressor TGs exhibited LV mass and LVEDD that resembled untreated WT, indicating protection from AZT CM. In contrast, Trx1‐DN mice exhibited baseline left ventricle hypertrophy which was decompensated to cardiac dysfunction with AZT therapy. There was minimal change in LVEDD. CONCLUSIONS: Data suggests that AZT produces cardiomyopathy and oxidative stress is integral to development of AZT cardiomyopathy. Trx2 overexpression protects against AZT cardiomyopathy and Trx1‐DN mice demonstrate increased AZT sensitivity in the heart. Trx2 overexpressors and Trx1‐DN mice together may represent an important model of CM from AZT or oxidative stress.