High density lipoprotein (HDL) exerts multiple vascular-protective effects in vivo. HDL promotes excess cholesterol efflux from peripheral tissues via transport to the liver for excretion, suppresses oxidative stress and inflammation, and enhances endothelial function. In murine and human subjects, receptor for AGE (RAGE) expression is upregulated in vascular and immune cells in non-diabetic and diabetic atherosclerosis. Studies in non-diabetic and diabetic LDL receptor (LDLR) null mice and apolipoprotein Apoe null mice revealed that blockade of ligand-RAGE interaction resulted in significant suppression of atherosclerosis. In this application, we will link for the first time ke roles for the receptor for advanced glycation end products (RAGE) to the biology of HDL prompted by three novel discoveries: first, RAGE deficient bone marrow derived macrophages (BMDMs) from non-diabetic or diabetic mice displayed significantly increased cholesterol efflux to ApoA1 and to HDL2 compared to RAGE expressing BMDMs. In parallel, mRNA levels for the two key cholesterol transporters, Abca1 and Abcg1, were H2-fold and >250-fold higher in RAGE null BMDMs vs. wild- type BMDMs, respectively. When RAGE expression was reduced by siRNAs in THP-1 human macrophages, significantly higher cholesterol efflux to ApoA1 and HDL2 resulted compared to treatment with scramble siRNAs. Second, in RAGE null BMDMs, levels of Mir33 were significantly lower than those found in wild-type mice control BMDMs;knockdown of RAGE expression in THP-1 macrophages resulted in highly significant reduction in MIR33 levels. Intriguingly, mRNA and protein levels of the Mir33 """"""""host gene"""""""" (Srebf2) did not differ between RAGE-expressing vs. RAGE null BMDMs, suggesting unique mechanisms of RAGE-dependent regulation of Mir33. Third, in seeking to identify the mechanisms by which macrophage RAGE attenuates tissue-damaging inflammatory responses, we discovered that incubation of BMDMs with RAGE ligand AGEs enhanced expression of pro-inflammatory """"""""M1"""""""" type macrophage markers and reduced expression of """"""""M2"""""""" type macrophage markers in a RAGE-dependent manner. We hypothesize that RAGE interferes with the benefits of HDL metabolism by reducing expression of key cholesterol transporters, consequences of which include: (1). reduced removal of cholesterol from atherosclerotic plaques leading to accelerated progression and reduced regression of atherosclerosis;and (2). maintenance of cholesterol-rich membrane properties that support RAGE-dependent signal transduction mechanisms and thereby potentiate """"""""M1"""""""" macrophage polarization and macrophage migration. We will test these concepts in this application using in vitro and in vivo approaches to discern the molecular mechanisms by which RAGE impacts regulation of Mir33/Abca1/Abcg1 and macrophage cholesterol efflux, polarization and migration and in vivo, reverse cholesterol transport and atherosclerosis. Taken together, this work will uncover novel therapeutic strategies to enhance HDL function and cardiovascular health.

Public Health Relevance

High density lipoprotein (HDL) exerts multiple vascular-protective effects in vivo. Based on our discoveries linking the RAGE pathway to diminished HDL function in vivo, our experimental approach is designed to uncover novel therapeutic strategies to enhance HDL function and cardiovascular health.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Liu, Lijuan
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Schmidt, Ann Marie (2018) Highlighting Diabetes Mellitus: The Epidemic Continues. Arterioscler Thromb Vasc Biol 38:e1-e8
Schmidt, Ann Marie (2017) 2016ATVBPlenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis an Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage. Arterioscler Thromb Vasc Biol 37:613-621
Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie (2017) Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 14:147-156
López-Díez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran et al. (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244-2252
Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie (2016) The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets 20:431-46
Litwinoff, Ems; Hurtado Del Pozo, C; Ramasamy, R et al. (2015) Emerging Targets for Therapeutic Development in Diabetes and Its Complications: The RAGE Signaling Pathway. Clin Pharmacol Ther 98:135-44
Schmidt, Ann Marie (2015) The growing problem of obesity: mechanisms, consequences, and therapeutic approaches. Arterioscler Thromb Vasc Biol 35:e19-23
Daffu, Gurdip; Shen, Xiaoping; Senatus, Laura et al. (2015) RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes. Diabetes 64:4046-60
Schmidt, Ann Marie (2014) Recent highlights of ATVB: diabetes mellitus. Arterioscler Thromb Vasc Biol 34:954-8
Schmidt, Ann Marie (2014) Skin autofluorescence, 5-year mortality, and cardiovascular events in peripheral arterial disease: all that glitters is surely not gold. Arterioscler Thromb Vasc Biol 34:697-9

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