AZT decreases rat myocardial cytochrome oxidase activity and increases beta-myosin heavy chain content.
AZT, a widely-utilized drug for the treatment of HIV infection, inhibits the polymerase responsible for mitochondrial DNA replication (mtDNA). The aim of this study was to assess myocardial alterations caused by this action. Ventricular muscle from rats treated for > or = 35 days with 1 mg/ml of AZT in their drinking water was analysed for cytochrome oxidase activity and the content of mRNAs for the nuclear-encoded cytochrome oxidase (COX) subunit VIc and the mitochondrial-encoded COX subunit III. In addition contractile protein expression was assessed by examining mRNA levels for alpha- and beta-myosin heavy chains (MHC). Changes in MHC mRNA levels were correlated with changes in alpha- and beta-MHC proteins and changes in myofibrillar ATPase activity. Results show that AZT caused a reduction in COX activity, COX subunit III mRNA, and mtDNA levels. There was no decrease in the COX subunit VIc mRNA. MHC expression was altered such that the relative content of beta-MHC protein and mRNA were increased. Accumulation of beta-MHC was reflected in the reduction of myofibrillar ATPase activity at pCa values of 5.875 and 6.125. These data demonstrate that AZT induces a reorganization of cardiac gene expression indicative of changes in cardiac contractile properties. The observed decreases in mtDNA levels along with mRNA for a mitochondrial-encoded protein and COX activity is consistent with the postulated mechanism whereby AZT induces a myopathy by diminishing mtDNA replication.
McCurdy
D T
DT
Cardiology Unit and Department of Molecular Physiology and Biophysics, University of Vermont, Given Building, Room E209, Burlington, VT 05405, USA.
Kennedy
J M
JM
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D015215:Zidovudine; D003576:Electron Transport Complex IV; D018995:Myosin Heavy Chains