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Chronic treatment with Azidothymidine (AZT) alters cytoskeletal proteins responsible for cardiac function
Author(s) -
McKee Edward E.,
Kamath Vasudeva,
Donahue Deborah L,
Tan John,
Zeng Erliang
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb138
Subject(s) - myosin , biology , toxicity , cytoskeleton , myosin light chain kinase , mitochondrion , actin , mitochondrial dna , zidovudine , cofilin , microbiology and biotechnology , medicine , actin cytoskeleton , biochemistry , virology , cell , gene , virus , viral disease
Metabolic complications resulting in cardiomyopathy are associated with long‐term treatment with the antiviral thymidine analog, AZT (3′‐azido‐3′ deoxythymidine; zidovudine). While mitochondrial toxicity is thought to be a major underlying cause, the molecular mechanism(s) are still ambiguous. We identified molecular and cellular changes associated with cardiac toxicity that occur after long‐term treatment. Adult male rats were chronically exposed to AZT in the drinking water for a period of six months. Mild changes in echocardiogram data suggested impaired cardiac function in AZT treated rats. Respiratory control rates and electron transport chain capacity as measured in isolated heart mitochondria by a high resolution respirometer were unchanged in the treated rats. There was also no change in the mitochondrial DNA copy numbers in treated animals. Interestingly, microarray analysis of total mRNA from heart samples presented with dramatic alterations in expression of mRNA in rats treated with AZT. Among these mRNAs, cytoskeletal protein mRNA alterations were evident in a number of pathways. Cytoskeletal/ contractile proteins such as actin, cofilin, profilin, myosin II, myosin light chain and myosin heavy chain were significantly altered contributing to contractile dysfunction. The role of mitochondrial toxicity in this model is unclear.