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

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 þ /À 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 þ /À 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 þ /À 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.

AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

“…AZT causes cardiac gene expression changes, altered DNA methylation, and changed SAM abundance. These results support and correlate mechanistically with pathophysiological changes of CM that we reported previously (20). In those studies, AZT caused CM to develop in wild-type mice (WT), while MCAT was able to prevent that CM.…”

“…Our previous work identified oxidative stress to be a critical component in the development of CM in AZT-treated mice (20). In those studies, pathophysiological changes in cardiac mass and structure were identified following 35 days of AZT treatment, and these changes could be attenuated or prevented by enhanced ROS scavenging by MCAT (7)(8)(9).…”

“…After 35 days, mice underwent cardiac physiological, histological, and molecular analyses according to our previously published protocols (20). All biomolecular analyses used left ventricle (LV) tissue sections.…”

“…(27). We showed that mitochondrial dysfunction from NRTIs increased reactive oxygen species (ROS) within the affected cell and amplified mitochondrial dysfunction in a feed-forward way (20). We prevented or attenuated NRTI toxicity both in vitro with exogenous metalloporphyrin antioxidants administration and in vivo with genetically engineered murine overexpression of mitochondrially targeted antioxidant enzymes (20,21,41).…”

Oxidative Stress and Novel Antioxidant Approaches to Reduce Diabetic Complications

“…Animal studies using transgenic mice over-expressing mitochondrially-targeted SOD and catalase have already shown the potential of this strategy, since these transgenic mice were associated with significant reductions in cardiac mitochondrial oxidative stress and improvements in left ventricular function after antiretroviral-induced cardiomyopathy (Kohler et al 2009). Indeed, the development of antioxidants that specifically target the matrix-facing inner surface of the mitochondrial membrane is hypothesised to protect against mitochondrial oxidative damage (Ross et al 2005).…”