Estrogen Plays a Crucial Role in Rab9-Dependent Mitochondrial Autophagy, Delaying Arterial Senescence

J Am Heart Assoc. 2021 Apr 6;10(7):e019310. doi: 10.1161/JAHA.120.019310. Epub 2021 Mar 15.


Background The risk of cardiovascular disease is known to increase after menopause. Mitochondria, which undergo quality control via mitochondrial autophagy, play a crucial role in the regulation of cellular senescence. The aim of this study was to investigate whether the effect of estrogen-mediated protection from senescence on arteries is attributed to the induction of mitochondrial autophagy. Methods and Results We used human umbilical vein cells, vascular smooth muscle cells, and 12-week-old female C57BL/6 mice. The administration of 17β-estradiol (E2) to cells inhibited cellular senescence and mitochondrial dysfunction. Furthermore, E2 increased mitochondrial autophagy, maintaining mitochondrial function, and retarding cellular senescence. Of note, E2 did not modulate LC3 (light chain 3), and ATG7 (autophagy related 7) deficiency did not suppress mitochondrial autophagy in E2-treated cells. Conversely, E2 increased the colocalization of Rab9 with LAMP2 (lysosomal-associated membrane protein 2) signals. The E2-mediated effects on mitochondrial autophagy were abolished by the knockdown of either Ulk1 or Rab9. These results suggest that E2-mediated mitochondrial autophagy is associated with Rab9-dependent alternative autophagy. E2 upregulated SIRT1 (sirtuin 1) and activated LKB1 (liver kinase B1), AMPK (adenosine monophosphate-activated protein kinase), and Ulk1, indicating that the effect of E2 on the induction of Rab9-dependent alternative autophagy is mediated by the SIRT1/LKB1/AMPK/Ulk1 pathway. Compared with the sham-operated mice, ovariectomized mice showed reduced mitochondrial autophagy and accelerated mitochondrial dysfunction and arterial senescence; these detrimental alterations were successfully rescued by the administration of E2. Conclusions We showed that E2-induced mitochondrial autophagy plays a crucial role in the delay of vascular senescence. The Rab9-dependent alternative autophagy is behind E2-induced mitochondrial autophagy.

Keywords: autophagy; estrogen; mitochondria; vascular senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / cytology*
  • Autophagy
  • Cells, Cultured
  • Cellular Senescence / physiology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Models, Animal
  • Signal Transduction
  • Up-Regulation*
  • rab GTP-Binding Proteins / metabolism*


  • rab9 protein, mouse
  • rab GTP-Binding Proteins