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Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation

2010; Lippincott Williams & Wilkins; Volume: 30; Issue: 4 Linguagem: Inglês

10.1161/atvbaha.109.202051

1524-4636

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

Erythrocyte Function and Pathophysiology

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.