THE Dpnwincn Interaction of atherogenic lipids with vascular cells plays a critical role in the formation and progression of atherosclerotic lesions. The goal of this project is to define the mechanisms by which CD36, a scavenger receptor for specific forms of oxidized phospholipid, mediates pro-atherogenic and pro-inflammatory responses. Recent studies suggest that scavenger receptor function in the vessel wall may be much more complex than simply serving as a conduit for uptake of atherogenic LDL particles and that intracellular signals triggered by the interaction of oxidized lipids with macrophage CD36 may induce responses that contribute to lesion development and plaque instability. New data obtained during the previous grant period shows that CD36-mediated signals led to activation of MAP kinases JNK-1 and -2. Given the central role of JNK in mediating pro-inflammatory responses and new studies linking pathogenesis of diabetes and insulin resistance to JNK activation, we propose that a CD36-dependent signaling pathway induced by the interaction of specific oxidized phospholipids with macrophages and adipocytes contributes to atherosclerosis and provides a mechanistic connection among atherosclerosis, inflammation, and insulin resistance. To explore this hypothesis, we will take advantage of unique reagents and expertise available through this new Program Project, including well characterized oxidized phospholipids that function as specific CD36 ligands, multiple cd36 null mouse strains, and technologies to transduce primary monocytes with cDNA and RNAi constructs. The 1st aim will define the role of specific oxidized lipid ligands in activating macrophage CD36, identify the molecular elements of the CD36 signaling pathway in macrophages, characterize the intracellular signaling pathways induced by CD36, and define the mechanisms by which CD36 cross talks with other vascular cell receptor signaling pathways, focusing on receptors of the innate immune system and insulin receptor. The 2nd aim will define mechanisms by which CD36 signals regulate specific macrophage functions;e.g. lipoprotein and apoptotic cell uptake, modulation of the inflammatory response, and cell migration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Silverstein, Roy L (2018) Oxidized Lipid Uptake by Scavenger Receptor CD36 (Cluster of Differentiation 36) Modulates Endothelial Surface Properties and May Contribute to Atherogenesis. Arterioscler Thromb Vasc Biol 38:4-5
Chen, Yiliang; Huang, Wenxin; Yang, Moua et al. (2017) Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. Arterioscler Thromb Vasc Biol 37:1462-1469
Silverstein, Roy L (2017) Linking Metabolic Dysfunction to Atherosclerosis Via Activation of Macrophage CD36 Gene Transcription by Retinol Binding Protein-4. Circulation 135:1355-1356
Ramakrishnan, Devi Prasadh; Hajj-Ali, Rula A; Chen, Yiliang et al. (2016) Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation. Arterioscler Thromb Vasc Biol 36:534-44
Gupta, Nilaksh; Li, Wei; McIntyre, Thomas M (2015) Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. Arterioscler Thromb Vasc Biol 35:2657-66
Chadwick, Alexandra C; Holme, Rebecca L; Chen, Yiliang et al. (2015) Acrolein impairs the cholesterol transport functions of high density lipoproteins. PLoS One 10:e0123138
Chen, Yiliang; Kennedy, David J; Ramakrishnan, Devi Prasadh et al. (2015) Oxidized LDL-bound CD36 recruits an Na?/K?-ATPase-Lyn complex in macrophages that promotes atherosclerosis. Sci Signal 8:ra91
Cathcart, Martha K; Bhattacharjee, Ashish (2014) Monoamine oxidase A (MAO-A): a signature marker of alternatively activated monocytes/macrophages. Inflamm Cell Signal 1:
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Gupta, Nilaksh; Li, Wei; Willard, Belinda et al. (2014) Proteasome proteolysis supports stimulated platelet function and thrombosis. Arterioscler Thromb Vasc Biol 34:160-8

Showing the most recent 10 out of 88 publications