Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation

Patricia G. Yancey, John Blakemore, Lei Ding, Daping Fan, Cheryl D. Overton, Youmin Zhang, MacRae F. Linton, Sergio Fazio

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Objective: The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis. Method and results: LRP-1-/- macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1-/- cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1 macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1 vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1-/- phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1 -/- lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion: Macrophage LRP-1-/- deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1-/- macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation.

Original languageEnglish (US)
Pages (from-to)787-795
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

Keywords

  • Apolipoprotein E
  • Apoptosis
  • Efferocytosis
  • Inflammation
  • LRP-1
  • Necrosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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