The Effect of Enhancing Mitophagy on Endothelial Function in Systemic Lupus Erythematosus (SLE)

SLE patients have been reported to have a high risk of CVD which is closely related to impaired endothelial function. Emerging evidence supports that impaired mitophagy contributes to the pathogenesis of SLE and endothelial dysfunction. Treatments known to induce autophagy/mitophagy were reported to improve endothelial function in mouse models of disease and in older humans. Those treatments, spermidine and rapamycin, enhance mitophagy but through different signaling pathways. Spermidine is a polyamine that stimulates the PINK1-Parkin-mediated pathway to activate mitophagy while rapamycin inhibits mTORC1 activity to induce mitophagy. However, the effect of these drugs on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) were randomly assigned into one of the two groups, control or treatment. Maximal responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed to measure the functional properties of thoracic aortas. Both interventions prevented endothelial dysfunction in SLE mice after 8 weeks of intervention. Although they were not significantly different, both interventions increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in the thoracic aorta of lupus mice. Vascular cell adhesion molecule 1 (Vcam1) level, one of the inflammatory markers in blood vessels was measured in all groups of mice. Lupus mice had significantly higher Vcam1 levels compared to healthy mice. Both spermidine and rapamycin, as they were shown in the previous literature, attenuated the level of Vcam1 in lupus mice with interventions when compared to untreated lupus mice. From both studies, lupus mice developed several lupus-like phenotypes such as splenomegaly and increased levels of autoantibodies (anti-dsDNA antibody and anti-Cardiolipin antibody) when compared to healthy control mice. Eight weeks of rapamycin treatment reduced the lupus phenotypes whereas spermidine did not show direct effects on lupus phenotypes. Lastly, we measured mitophagy markers in abdominal aortas from all groups. Spermidine altered the level of mitophagy markers (LC3II/I and Parkin) in the lupus treatment group. With rapamycin, the changes in the level of mitophagy-related markers (p-ULK1, p62, and LC3II/I) did not significantly change. Results from both studies demonstrate the beneficial effects of spermidine and rapamycin treatment on endothelial function and inflammatory responses in SLE mice. Although there is a necessity for further study to determine the mechanism of mitophagy, these two interventions hold potential therapeutic value for targeting SLE-induced endothelial dysfunction and increased cardiovascular risk in SLE patients.

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