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Resistance to cardiac doxorubicin damage in a Gsta4 knockout mouse
Author(s) -
Benes Helen,
Vuong Mai,
Telemaque Sabine,
Marsh James D,
Zimniak Piotr,
Boerma Marjan
Publication year - 2010
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.24.1_supplement.712.1
Subject(s) - cardiac function curve , basal (medicine) , cardiomyopathy , oxidative stress , knockout mouse , endocrinology , 4 hydroxynonenal , medicine , glutathione , doxorubicin , chemistry , pharmacology , lipid peroxidation , heart failure , biochemistry , receptor , chemotherapy , enzyme , insulin
4‐hydroxynonenal (4‐HNE) mediates both pathological effects of oxidative stress and signaling from mitochondrion to nucleus to elicit transcriptional responses that are largely controlled by Nrf2. As elevated levels of 4‐HNE are associated with several cardiovascular diseases, metabolism of 4‐HNE is critical. The murine glutathione transferase A4–4 (GSTA4–4) exhibits very high levels of 4‐HNE‐conjugating activity, which is reduced in the hearts of Gsta4 knockout (KO) mice. KO mice exhibited no cardiac pathology; cardiac 4‐HNE levels were no different in WT and KO mice. We examined how Gsta4 KO mice react to high cardiac 4‐HNE accumulation following chronic administration of doxorubicin (DOX) (5 mg/kg, 4 weekly injections). Cardiac function was assessed by echocardiography. While untreated mice exhibited similar basal cardiac function, WT mice were more sensitive to DOX, resulting in a significantly higher mortality rate. Ejection Fraction (EF) fell in both groups after the first DOX injection. At day 21, EF was significantly lower in WT mice as compared to baseline whereas EF in KO mice recovered to the basal value. Changes in fractional shortening correlated with EF in both groups. We concluded that Gsta4 KO mice exhibited resistance to DOX cardiomyopathy and will explore how Nrf2‐induction of SOD and catalase may contribute to a cardioprotective effect. Supported by a College of Medicine Pilot Study Grant.