| First Author | Yancey PG | Year | 2010 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 30 |
| Issue | 4 | Pages | 787-95 |
| PubMed ID | 20150557 | Mgi Jnum | J:172263 |
| Mgi Id | MGI:5005054 | Doi | 10.1161/ATVBAHA.109.202051 |
| Citation | Yancey PG, et al. (2010) Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler Thromb Vasc Biol 30(4):787-95 |
| abstractText | 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-1 beta, IL-6, and tumor necrosis factor-alpha 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. CONCLUSIONS: 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. |
