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. 2009 Jul;89(7):782-90.
doi: 10.1038/labinvest.2009.39. Epub 2009 Apr 27.

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

James J Kohler  1 , Ioan Cucoranu, Earl Fields, Elgin Green, Stanley He, Amy Hoying, Rodney Russ, Allison Abuin, David Johnson, Seyed H Hosseini, C Michael Raper, William Lewis
Affiliations

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

James J Kohler et al. Lab Invest. 2009 Jul.

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 H(2)O(2), 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 H(2)O(2) 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 H(2)O(2), LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H(2)O(2) 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 H(2)O(2) abundance, oxidative stress from H(2)O(2) is crucial pathogenetically in AZT-induced mitochondrial CM.

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Figures

Figure 1
Figure 1
Final body weight after 5 weeks AZT treatment. Final body weights after 5 weeks treatment with vehicle and/or AZT were measured for individual mice and grouped by cohorts. All cohorts exhibited equivalent final body weights.
Figure 2
Figure 2
Cardiac functional phenotype in SOD2+/− KO, SOD2-OX and mCAT TGs with and without AZT: SOD2+/− KO, SOD2-OX, mCAT TGs and WT mice were treated with vehicle or with vehicle + AZT through gavage (0.22 mg per day; 35 days) that was administered in ‘2 by 2’ factorial protocols. (a) Echocardiographically determined LV mass increased in vehicle-treated SOD2+/− KOs compared with vehicle-treated WTs. AZT treatment increased LV mass in WTs. AZT treatment further increased LV mass in SOD2+/− KOs (*P<0.001). SOD2-OX and mCAT TGs both seemed protected from AZT-induced toxicity. (b) SOD2+/− KO LVEDD was unchanged from LVEDD in WTs. LVEDD was significantly increased by AZT in the SOD2+/− KO (#P<0.05). SOD2-OX and mCAT TGs remained unchanged from WTs regardless of treatment.
Figure 3
Figure 3
Oxidative phenotype of CM in SOD2+/− KO, SOD2-OX and mCAT TGs with and without AZT. (a) Mitochondrial H2O2 abundance in heart samples from AZT-treated SOD+/− KO increased compared with H2O2 abundance in mitochondrial samples from vehicle-treated SOD+/− KOs or WT controls (*P<0.01). Mitochondrial H2O2 abundance remained unchanged in SOD2-OX or decreased in mCAT TGs even after AZT treatment. (b) Decreased cardiac aconitase activity was found in AZT-treated WTs and SOD2+/− KOs (vehicle or AZT-treated) compared with vehicle-treated WTs (P<0.05).
Figure 4
Figure 4
Structural phenotypes of CM in SOD2+/− KO, SOD2-OX and mCAT TGs with and without AZT. Representative photomicrographs from ventricular cardiac myocytes of each cohort treated with and without AZT showed disrupted myocardial fibers and myocytolysis in AZT-treated WTs. Pathological changes were exacerbated in SOD2+/− KO. SOD2-OX and mCAT TGs maintained structural integrity of their myocardial fibers even with AZT treatment. (H&E; original magnification: ×600).
Figure 5
Figure 5
Ultrastructural changes in cardiac mitochondria in SOD2+/− KO, SOD2-OX and mCAT TGs with and without AZT. Representative TEM profiles of cardiac myocytes from each cohort (with and without AZT) showed cardiac myocytes with disrupted sarcomeres, tubules and mitochondria in vehicle-treated SOD2+/− KOs that was worsened by AZT treatment. Changes in cardiac myocytes from SOD2-OX and mCAT TGs (regardless of treatment) were unremarkable and resembled myocytes from vehicle-treated WTs. (original magnification: ×23300).
Figure 6
Figure 6
Schematic summary of the proposed mitochondrial mechanisms of AZT toxicity leading to CM. Highlighted are the roles of SOD2 and mCAT overexpression, and/or KO in regulation of oxidative stress (eg H2O2 production) in the mitochondria that leads to disruption of mitochondrial biogenesis and CM (adapted from 34).
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