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2013 Research Abstract

Nucleoside Reverse Transcriptase Inhibitor-Induced Premature Senescence in Endothelial Cells via Mitochondrial Oxidative Stress

Investigator: Stephen Xue

Mentor: Tammy Dugas, PhD

Abstract: Long-term use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) is known to induce mitochondrial damage in endothelial cells, ultimately resulting in endothelial dysfunction and atherosclerosis. Though the mechanism of NRTI-induced effects on endothelial cells is not well understood, prior work suggests that mitochondrially-compartmentalized oxidative stress and premature cellular senescence may be involved. We thus examined the role of NRTI treatment in stress-induced premature senescence in endothelial cells and investigated the potential of adjunct utilization of the antioxidant coenzyme Q10 (CoQ10) to combat NRTI-induced endothelial toxicity. Co-treatment of human aortic endothelial cells (HAEC) with CoQ10 was found to rescue cells from NRTI-induced increases in ROS levels and decreases in ATP production and oxygen consumption. In addition, we found that NRTIs increased levels of endothelin-1 (ET-1), a marker for endothelial cell dysfunction, but this effect was also reversed by CoQ10 co-treatment. Interestingly, treatment of HAEC with the NRTI zidovudine (AZT) induced selective mitochondrial autophagy, or mitophagy. AZT treatment for 6-8 h increased lysosomal activity, while 8 hour treatment was found to increase colocalization of mitochondria with lysosomes, an indicator of mitophagy. The LC3-II/LC3-I ratio, a marker of autophagosomal activity, was also increased in treated cells. Finally, NRTI treatment was found to accelerate the onset of cellular senescence, while CoQ10 co-treatment ameliorated this effect. These findings suggest that NRTI-induced autophagic degradation of mitochondria may be involved in endothelial dysfunction caused by NRTI treatment, and that this damage likely results from oxidant injury. Moreover, oxidative stress induced by NRTIs enhances premature senescence in endothelial cells, and CoQ10 is able to attenuate this response as well.

Last Updated: 6/19/14

Updated on June 19, 2014.