Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy.
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.
Kohler
James J
JJ
Department of Pathology, Emory University, Atlanta, GA, USA.
Cucoranu
Ioan
I
Fields
Earl
E
Green
Elgin
E
He
Stanley
S
Hoying
Amy
A
Russ
Rodney
R
Abuin
Allison
A
Johnson
David
D
Hosseini
Seyed H
SH
Raper
C Michael
CM
Lewis
William
W
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015215:Zidovudine / Q000633:toxicity*; D000099156:Superoxide Dismutase 2
D000154:Aconitate Hydratase; D019380:Anti-HIV Agents; D002374:Catalase; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D015215:Zidovudine; D000099156:Superoxide Dismutase 2