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MCU-dependent mitochondrial calcium uptake-induced mitophagy contributes to apelin-13-stimulated VSMCs proliferation

Zhe Chen1, Qionglin Zhou1, Jun Chen1

  • 1Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.

Vascular Pharmacology
|March 20, 2022
PubMed

Insights

Apelin-13 stimulates vascular smooth muscle cell proliferation via mitochondrial calcium uptake and mitophagy. This process involves the mitochondrial calcium uniporter (MCU) and key mitophagy proteins, offering potential therapeutic targets for cardiovascular diseases.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Dynamics
  • Cellular Signaling

Background:

  • Apelin and its receptor APJ are crucial in cardiovascular function.
  • Previous research linked mitophagy to apelin-13-induced VSMC proliferation.
  • The precise mechanism of apelin-13's regulation of mitophagy in VSMCs remained unclear.

Purpose of the Study:

  • To elucidate the role of mitochondrial calcium uniporter (MCU)-dependent mitophagy in apelin-13-induced VSMC proliferation.
  • To investigate the signaling pathways involved in this process.
  • To assess the in vivo relevance in an atherosclerosis model.

Main Methods:

  • Investigated apelin-13's effects on MCU expression and mitochondrial calcium uptake in VSMCs.
  • Assessed mitophagy markers (Drp1, PINK1, Parkin) and mitochondrial ROS (mtROS) levels.
  • Utilized pharmacological inhibitors (Mito-TEMPO, mdivi-1, Ru360) and genetic silencing (siRNA).
  • Evaluated apelin-13's impact on atherosclerotic plaque in ApoE knockout mice.

Main Results:

  • Apelin-13 upregulated MCU, enhancing mitochondrial calcium uptake and subsequent mtROS production.
  • This led to increased mitophagy, evidenced by elevated Drp1, PINK1, and Parkin.
  • Inhibition of MCU, Drp1, or mitophagy pathways attenuated apelin-13-induced VSMC proliferation.
  • Apelin-13 exacerbated atherosclerosis in ApoE-/- mice, an effect reversed by MCU inhibition.

Conclusions:

  • Apelin-13 stimulates VSMC proliferation through a pathway involving MCU-mediated mitochondrial calcium uptake and mitophagy.
  • This mechanism contributes to the development of atherosclerosis.
  • Targeting the MCU-mitophagy axis presents a potential therapeutic strategy for cardiovascular diseases.
Keywords:
Apelin/APJMCUMitochondrial ROSMitophagyVSMCs proliferation

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