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

Yancey PG, Blakemore J, Ding L, Fan D, Overton CD, Zhang Y, Linton MF, Fazio S
Arterioscler Thromb Vasc Biol. 2010 30 (4): 787-95

PMID: 20150557 · PMCID: PMC2845445 · DOI:10.1161/ATVBAHA.109.202051

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.

MeSH Terms (25)

Animals Apolipoproteins E Apoptosis Atherosclerosis Cells, Cultured Cell Survival Enzyme Activation Female Inflammation In Situ Nick-End Labeling Interleukin-1beta Interleukin-6 Lipopolysaccharides Lipoproteins, LDL Low Density Lipoprotein Receptor-Related Protein-1 Macrophages, Peritoneal Mice Mice, Knockout Necrosis Phagocytosis Phosphorylation Proto-Oncogene Proteins c-akt Receptors, LDL Tumor Necrosis Factor-alpha Tumor Suppressor Proteins

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