Metformin Alleviates Stress-Induced Premature Senescence of Vascular Endothelial Cells by Regulating Mitocytosis
Abstract
Stress-induced premature senescence (SIPS) of endothelial cells can cause endothelial dysfunction. As a first-line antidiabetic agent, the specific role of metformin in SIPS has not yet been clarified. In this study, an in vitro SIPS model was induced by exposing human umbilical vein endothelial cells (HUVECs) to hydrogen peroxide (H2O2), and the effects of metformin on cell senescence, proliferation, migration, tube formation, and mitochondrial function were evaluated. Gene expressions altered by metformin were profiled via transcriptome sequencing. Specifically, the potential involvement of migrasome-mediated mitocytosis in metformin-driven effects was examined using confocal microscopy and siRNA-mediated silencing. The results showed that metformin significantly reduced SA-β-gal activity and restored the migration and tube-forming capacities of H2O2-induced senescent HUVECs. Moreover, metformin regulated mitochondrial dynamics, restored mitochondrial membrane potential, and attenuated intracellular oxidative stress. Notably, transcriptomic and functional analyses suggested that metformin enhanced migrasome formation and migrasome-mediated mitocytosis. Inhibition of migrasome formation by siTSPAN4 abolished the protective effect of metformin against SIPS. Collectively, these findings demonstrate that metformin alleviates early SIPS-associated changes in HUVECs and suggest that migrasome-mediated mitocytosis contributes to this protection by ameliorating mitochondrial…
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