MitoQ Has Diverse Effects on H2O2-Induced Oxidative Stress and the NRF2 Signalling Pathway in Aortic Smooth Muscle Cells of Different Origins

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Oxidative stress plays a central role in the development and progression of abdominal aortic aneurysms (AAA), as it severely impairs the function and survival of vascular smooth muscle cells (VSMCs). MitoQ (mitoquinone mesylate), a mitochondria-specific antioxidant, was shown to reverse age-related arterial stiffening and improve vascular endothelial function, among other things, by interacting with the NRF2 signalling pathway. The aim of this study was to compare how long-term treatment with low doses of MitoQ affects the NRF2 stress response in VSMCs, derived from different origins (AAA-SMC, healthy aortic SMC, and immortalized VSMC (iHAoSMC)). We found a significant reduction in NRF2 and KEAP1 levels in the aortic wall of patients with AAA, accompanied by increased 8-OHdG levels, indicating defects in the response to oxidative stress. In contrast, relative NRF2 expression in tissue extracts and VSMC-enriched areas was higher in patients with AAA than in healthy aortic tissue. In vitro, baseline NRF2 protein levels were significantly higher in AAA-SMC and in iHAoSMC than in VSMC from healthy aorta, whereas NRF2 activity did not differ between AAA-derived and healthy VSMC. AAA-derived SMC were found to be less vulnerable against toxic concentrations of MitoQ than healthy VSMC, and the cell viability was differentially affected by H2O2. Acute oxidative stress by H2O2 increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC. Pre-treatment of the cells for 7 days with low-dose (10 nM) MitoQ resulted in significantly increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC, which was accompanied by a significant reduction of ROS production, particularly in AAA-derived SMC. Our data demonstrate that prolonged treatment with low doses of MitoQ has a protective effect, particularly on VSMCs from AAA, without affecting healthy aortic VSMCs. Moreover, immortalized cells can be used as a model for investigating oxidative stress responses in AAA-SMC, even though they do not react in exactly the same way. Overall, our findings confirm the cytoprotective potential of MitoQ to limit oxidative stress, particularly in AAA-SMC that is clinically observed in the abdominal aneurysm wall.

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