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)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057986-16
Application #
8602846
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
1998-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2014
Total Cost
$361,532
Indirect Cost
$129,781
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Kaseda, Ryohei; Tsuchida, Yohei; Yang, Hai-Chun et al. (2018) Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. BMC Nephrol 19:17
Fazio, Sergio; Pamir, Nathalie (2016) HDL Particle Size and Functional Heterogeneity. Circ Res 119:704-7
Zhu, Lin; Giunzioni, Ilaria; Tavori, Hagai et al. (2016) Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-? Inhibition. Arterioscler Thromb Vasc Biol 36:1483-95
Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman et al. (2016) Local effects of human PCSK9 on the atherosclerotic lesion. J Pathol 238:52-62
Shapiro, Michael D; Fazio, Sergio (2016) From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk. Circ Res 118:732-49
Bartlett, Jacquelaine; Predazzi, Irene M; Williams, Scott M et al. (2016) Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights From the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes 9:206-212
Jahangir, Eiman; Lipworth, Loren; Edwards, Todd L et al. (2015) Smoking, sex, risk factors and abdominal aortic aneurysms: a prospective study of 18?782 persons aged above 65 years in the Southern Community Cohort Study. J Epidemiol Community Health 69:481-8
Tavori, Hagai; Su, Yan Ru; Yancey, Patricia G et al. (2015) Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL. J Lipid Res 56:635-43
Kaseda, Ryohei; Jabs, Kathy; Hunley, Tracy E et al. (2015) Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism 64:263-73
Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G et al. (2015) Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. Atherosclerosis 242:56-64

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