The atheroma macrophage lives in a peculiar environment, where cholesterol excesses trigger diverging signals of active phagocytosis and inflammatory bursts. During the previous cycles of this grant, we have focused on two proteins that have both cooperative and independent functions on cellular cholesterol trafficking and regulation of inflammation, apoE and LRP1. ApoE is an LXR-regulated protein, highly expressed in macrophages under conditions of cholesterol loading, with the ability to drive cholesterol efflux from the cell and with direct anti-atherogenic effects. However, apoE can also associate with atherogenic lipoproteins and then bind to internalizing receptors such as LDLR and LRP1, thus driving cholesterol back into the cell. LRP1, a receptor for multiple ligands, acts in the liver as a back-up system for the LDLR to clear remnant lipoproteins. Hepatic LRP1 needs locally produced apoE to clear incoming remnants already enriched in plasma-derived apoE, whereas LDLR clears apoE-containing lipoproteins even in the absence of locally produced apoE. With the working hypothesis that apoE and LRP1 interact more intricately than in a relation between lipoprotein ligand and its internalizing receptor, we moved to an experimental stage where LDLR is not the dominant lipoprotein receptor and where the interaction may have complex biological consequences, the atheroma macrophage. We demonstrated that absence of LRP1 in macrophages increases atherogenesis, a paradoxical effect given that it also reduced internalization of remnant lipoproteins and increased expression of apoE. These data suggest both that the effect of LRP1 is not linked to bulk cholesterol transport and that the vascular effect of apoE is mediated by an interaction with LRP1. We were surprised to determine that the latter is not true, as the deletion of apoE aggravated the atherogenic phenotype of LRP1-/- macrophages, thus suggesting that these proteins have independent and additive effects that regulate vascular homeostasis. The plaques of apoE-/-/LRP1-/- mice showed a uniquely severe pattern of macrophage apoptosis with a deficit in the internalization of apoptotic bodies by viable phagocytes. An effect unique to LRP1 was noted on the induction of inflammatory responses, as mice carrying LRP1-/- macrophages showed significantly higher numbers of circulating and splenic pro-inflammatory Ly6chi monocytes and arterial wall Ly6chi and CCR2 positive macrophages. Another effect unique to LRP1 was noted on the regulation of prosaposin trafficking. Prosaposin leads to the formation of the saposins (sphingolipid activator proteins), critical for processing and clearance of lysosomal and membrane sphingolipids. This pathway is intertwined with the autophagic machinery, recently shown to regulate cholesterol efflux from foam cells, and with the inflammatory response. The proposed studies aim at characterizing the molecular pathways responsible for the exaggerated cell death, inflammation, and dysfunctional clearance of cell debris caused by the absence of LRP1. We strive to understand the factors that regulate bulk plaque regression.

Public Health Relevance

The atherosclerotic lesion, which causes heart attacks and strokes, is a complex tissue containing live cells, such as macrophages derived from the blood, and sub-cellular material, such as lipoproteins and debris from dead cells. Reduction in plaque size can be accomplished by blocking entry of new material and increasing exit of cholesterol, egress of live cells, and removal of dead bodies. Our studies focus on the interaction of two proteins, apoE and LRP1, which regulate cholesterol trafficking, cell viability, and removal of debris. These studies may identify therapies to shrink the plaque and reduce heart attacks.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
7R01HL057986-17
Application #
8875134
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
None
Type
Schools of Medicine
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
Fazio, Sergio; Tavori, Hagai (2014) Peeking into a cool future: genome editing to delete PCSK9 and control hypercholesterolemia in a single shot. Circ Res 115:472-4
Prins, Petra A; Hill, Michael F; Airey, David et al. (2014) Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure. PLoS One 9:e84517
Tavori, Hagai; Fan, Daping; Giunzioni, Ilaria et al. (2014) Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice. J Lipid Res 55:2073-81
Babaev, Vladimir R; Hebron, Katie E; Wiese, Carrie B et al. (2014) Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice. J Lipid Res 55:2296-308
Fazio, Sergio; Linton, MacRae F (2013) Killing two birds with one stone, maybe: CETP inhibition increases both high-density lipoprotein levels and insulin secretion. Circ Res 113:94-6
Predazzi, Irene M; Rokas, Antonis; Deinard, Amos et al. (2013) Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data. Circ Cardiovasc Genet 6:299-307
Fazio, Sergio; Linton, MacRae F (2012) Inhibition of apolipoprotein(a) synthesis by farnesoid X receptor and fibroblast growth factor 15/19: a step toward selective lipoprotein(a) therapeutics. Arterioscler Thromb Vasc Biol 32:1060-2
Babaev, Vladimir R; Whitesell, Richard R; Li, Liying et al. (2011) Selective macrophage ascorbate deficiency suppresses early atherosclerosis. Free Radic Biol Med 50:27-36
Sampson, Uchechukwu K; Perati, Prudhvidhar R; Prins, Petra A et al. (2011) Quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta for studies of abdominal aortic aneurysms and related arterial diseases. J Ultrasound Med 30:773-84
Yamamoto, Suguru; Yancey, Patricia G; Zuo, Yiqin et al. (2011) Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. Arterioscler Thromb Vasc Biol 31:2856-64

Showing the most recent 10 out of 76 publications