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 language | English (US) |
---|---|
Pages (from-to) | 787-795 |
Number of pages | 9 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 30 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2010 |
Externally published | Yes |
Keywords
- Apolipoprotein E
- Apoptosis
- Efferocytosis
- Inflammation
- LRP-1
- Necrosis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine