Myocardial fibrosis and effect of AZT in myocardium of Y995CB mouse
Pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs), one of the primary classes of HIV/AIDS antiretroviral drugs, are known to cause mitochondrial toxicity by inhibiting polymerase gamma during extending mitochondrial DNA replication. Extensive, prolonged use of NRTIs, such as zidovudine (3'-azido-2',3'-deoxythymidine; AZT), is associated with cardiovascular complications, such as dilated cardiomyopathy, the most common form of heart failure in which cardiac fibrosis is seen. Moreover, cardiac fibrosis is part of the pathological response of the heart during the progression of heart failure. Thus, we hypothesized that AZT treatment will contribute to the progression of cardiac fibrosis indirectly. Our study specifically focused on the effects of AZT and the development of cardiac fibrosis in the myocardium of wildtype (WT) and Y955CB transgenic mice (TG). Y955CB TG expresses a dominant negative cardiac specific mutant mitochondrial DNA polymerase gamma and were used to enhance the mtDNA toxic effect of AZT. To estimate fibrosis, myocardial collagen levels in each treatment group were assessed using both the hydroxyproline assay and histological image analysis. WT mice treated with AZT 0.22 mg/day for 35 days revealed no change in the level of hydroxyproline. However, a significant increase in hydroxyproline abundance correlated with histologically detectable fibrosis in vehicle-treated Y955CB TG mice. Interestingly, there was no additional increase in the abundance of collagen in AZT-treated Y955CB mice. Taken together, these data demonstrate that Y955CB TG displays an increase in the collagen level of the heart, concomitant with its documented cardiomyopathy. However AZT treatment was insufficient to increase the abundance of collagen in the heart.
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