¹Department of Pathology, Emory University, Atlanta, GA, USA

Correspondence: Dr W Lewis, MD, Department of Pathology, Emory University School of Medicine, 7117 Woodruff Memorial Building, 101 Woodruff Circle, Atlanta, GA 30322, USA. E-mail: wlewis@emory.edu

²These authors contributed equally to this work.

Received 3 February 2009; Revised 14 March 2009; Accepted 24 March 2009; Published online 27 April 2009.

Abstract

Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2^+/- KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H₂O₂, aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H₂O₂ increased and aconitase was inactivated in SOD2^+/- KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H₂O₂, LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H₂O₂ in SOD2^+/- KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H₂O₂ abundance, oxidative stress from H₂O₂ is crucial pathogenetically in AZT-induced mitochondrial CM.