Endophilin-A2-mediated increase in scavenger receptor expression contributes to macrophage-derived foam cell formation

Atherosclerosis. 2016 Nov:254:133-141. doi: 10.1016/j.atherosclerosis.2016.10.009. Epub 2016 Oct 6.

Abstract

Background and aims: Macrophage-derived foam cell formation (MFCF) is a crucial step in the pathogenesis of atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors is indispensable for MFCF. Endophilin-A2 has been reported to regulate clathrin-mediated endocytosis (CME). In this study, we tested the hypothesis that endophilin-A2 regulates oxLDL uptake and MFCF by mediating CME of oxLDL-scavenger receptor complexes.

Methods: In vitro MFCF was induced by oxLDL treatment. Involvement of endophilin-A2 in oxLDL cytomembrane binding, cellular uptake, and MFCF was evaluated by manipulation of endophilin-A2.

Results: Endophilin-A2 was involved in MFCF via scavenger receptor CD36 and scavenger receptor-A (SR-A)-mediated positive feedback pathways. We observed that oxLDL triggered interaction of endophilin-A2 with CD36 or SR-A, and induced an endophilin-A2-dependent activation of the apoptosis signal-regulating kinase-1 (ASK1)/Jun N-terminal kinase (JNK)/p38 signaling pathway. The activation of ASK1-JNK/p38 signal increased expression of both CD36 and SR-A, which promoted oxLDL cytomembrane binding, cellular uptake, and MFCF. In the absence of oxLDL, endophilin-A2 up-regulated the expression of receptors and Dil-oxLDL binding and uptake, but not the intracellular accumulation of lipids. In the presence of oxLDL, the CME inhibitors pitstop2 and ikarugamycin mimicked the inhibiting effect of endophilin-A2 knockdown and eliminated the elevating effect of endophilin-A2 overexpression on oxLDL uptake and MFCF.

Conclusions: Endophilin-A2 was identified as a novel molecule regulating MFCF by mechanisms attributable to CME and beyond CME.

Keywords: ASK1; Endophilin-A2; Foam cell formation; Scavenger receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / metabolism
  • Endocytosis
  • Foam Cells / cytology*
  • Gene Expression / drug effects
  • Gene Expression Regulation
  • Healthy Volunteers
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lactams / chemistry
  • Lipids / chemistry
  • Lipoproteins, LDL / chemistry
  • Lipoproteins, LDL / metabolism
  • Macrophages / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Scavenger / metabolism*
  • Scavenger Receptors, Class A / metabolism
  • Sulfonamides / chemistry
  • Thiazolidines / chemistry

Substances

  • CD36 Antigens
  • Intracellular Signaling Peptides and Proteins
  • Lactams
  • Lipids
  • Lipoproteins, LDL
  • Receptors, Scavenger
  • SH3GL1 protein, human
  • Scavenger Receptors, Class A
  • Sulfonamides
  • Thiazolidines
  • oxidized low density lipoprotein
  • pitstop 2
  • ikarugamycin