PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions

J Cell Physiol. 2019 Jun;234(6):8668-8682. doi: 10.1002/jcp.27527. Epub 2018 Nov 19.

Abstract

Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin-13 stimulation. Mechanistically, apelin-13 increases p-AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin-1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin-13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin-13 impairs mitophagy and prevents proliferation. Additional, apelin-13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor-1(Mdivi-1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE-/- mice with apelin-13 accelerates atherosclerotic lesions, increases p-AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1-/- mutant mice with apelin-13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin-mediated mitophagy promotes apelin-13-evoked human aortic VSMC proliferation by activating p-AMPKα and exacerbates the progression of atherosclerotic lesions.

Keywords: AMPKα; Apelin-13; atherosclerosis (AS); mitophagy; vascular smooth muscle cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Aortic Diseases / enzymology*
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Case-Control Studies
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Mitochondria, Muscle / drug effects*
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / ultrastructure
  • Mitophagy / drug effects*
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / ultrastructure
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / ultrastructure
  • Phosphorylation
  • Plaque, Atherosclerotic
  • Protein Kinases / deficiency
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Intercellular Signaling Peptides and Proteins
  • apelin-13 peptide
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • AMP-Activated Protein Kinases