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Roy L. Silverstein, MD

Roy L. Silverstein, MD

Senior Investigator

John and Linda Mellowes Professor and Chairman
Department of Medicine
Medical College of Wisconsin

Education and training

MD, Emory University School of Medicine, 1979
Residency in Internal Medicine, Hematology and Medical Oncology, New York Hospital Cornell Medical Center

Contact Us

Roy L. Silverstein, MD

Senior Investigator
Email (414) 805-0518 Fax: (414) 805-0524

  • Research Interests

    Thrombosis, Hemostasis and Vascular Biology

    Our laboratory studies basic pathophysiologic mechanism underlying common vascular diseases, especially thrombosis and atherosclerosis. The work focuses on a specific cellular receptor known as CD36. This is the defining member of the Type 2 scavenger receptor family and is expressed on the surface of platelets, monocytes, macrophages, capillary endothelial cells, adipocytes and myocytes. CD36 is a multifunctional receptor that recognizes three major classes of ligand: proteins containing the so-called thrombospondin structural homology domain (TSR), free fatty acids, and oxidized phospholipids that are presented by exogenous pathogens and endogenous “danger signals”.   Our lab has developed a “tool kit” to study this protein in vivo and in vitro, including genetic knockout mice crossed into several disease model backgrounds, specific antibodies and shRNA reagents, and highly specific ligands. We are currently working on two major projects funded by NIH, American Heart Association, and Advancing a Healthier Wisconsin.

    A major project in the laboratory focuses on the role of CD36 on platelets. Our lab discovered that platelet CD36 serves to recognize endogenous “danger signals” generated during inflammation, oxidant stress, diabetes, and cancer. These signals include oxidized LDL (oxLDL), advanced glycated proteins, and cell-derived microparticles. Interaction of these molecules with CD36 initiates a complex signaling pathway involving Src-family kinases, MAP kinases, a guanine nucleotide exchange factor known as Vav, resulting in intracellular generation of reactive oxygen species (ROS) which then results and enhanced platelet reactivity and thrombosis. Studies of mouse models and human populations have linked this pathway to important pro-thrombotic states, including diabetes, atherosclerosis and inflammation. We are using chemical biology techniques to explore downstream protein modifications induced in platelets by CD36-generated ROS with the goal of identifying novel therapeutic and diagnostic targets.

    The second project in the lab focuses on the role of CD36 in promoting atherosclerosis, the disease responsible for heart attack and stroke. We have shown in mouse models and cell models that CD36 binds to oxidized LDL (so-called bad cholesterol) and promotes cholesterol accumulation in macrophages and atherosclerotic plaque formation. Current studies focus on understanding the cellular mechanisms of CD36’s pro-atherogenic function. We have discovered a novel signaling pathway that dramatically alters macrophage migration and promotes oxidant stress in the blood vessel wall and linked this to changes in intracellular metabolism and macrophage polarization. We hope that we can target this pathway to promote atherosclerotic plaque resolution. 

  • Grant Support
    • Advancing a Healthier Wisconsin Endowment Signature Program Award:
      Metabolic Control of Inflammation in Atherosclerosis by Macrophage Scavenger Receptors
    • NIH – R01 HL126645:  MRP-14, CD36 and Thrombosis    
    • NIH – R01 HL142152: ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury
  • Lab

    Wenxin Huang, PhD
    Sr Research Associate

    Yiliang Chen, PhD
    Research Scientist I

    Yiqiong Zhao 
    Research Lab Technician

    Yanjuan Hou, MD, PhD
    Postdoctoral Fellow

  • Publications

    Selected Publications:

    • Febbraio, M., Podrez, E.A., Smith, J.D., Hazen, S.L., Hoff, H.F., Sharma, K., Hajjar, D.P., and Silverstein R.L. 2000. Targeted disruption of the Class B scavenger receptor, CD36, protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105:1049-1056.
    • Finnemann, S.C. and Silverstein R.L. 2001. Differential roles of CD36 and αvβ5 integrin in photoreceptor phagocytosis by the retinal pigment epithelium. J. Exp. Med. 194:1289-1298.
    • Greenberg, M.E., Sun, M., Zhang, R., Febbraio, M., Silverstein, R.L., and S.L. Hazen. 2006. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage dependent phagocytosis of apoptotic cells. J. Exp Med. 203(12): 2613-25
    • Podrez, E.A., Byzova, T.V., Febbraio, M., Salomon, R.G., Ma, Y., Valiyaveettil, M., Poliakov, E., Sun, M., Finton, P.J., Curtis, B.R., Chen, J., Zhang, R., Silverstein, R.L., and S.L. Hazen. 2007. Platelet CD36 links hyperlipidemia, oxidant stress and a pro-thrombotic phenotype. Nature Medicine 13(9):1086-1095.
    • Ghosh, A., Li, W., Febbraio, M., Espinola, R.G., McCrae, K., and Silverstein R.L. 2008. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in vivo. J. Clinical Investigation 118 (5):1934-1943.
    • Chen, K., Febbraio, M., Li, W., and Silverstein R.L. 2008. A specific CD36-dependent signaling pathway is required for platelet activation by oxidized LDL. Circulation Research 102;1512-1519.
    • Park, Y.M., Febbraio, M. and Silverstein R.L.   2009. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and contributes to macrophage trapping in the arterial intima. J. Clin. Invest. 119(1):136-145.
    • Kashyap, S.R., Ioachimescu, A., Gornik, H.L., Gopan, T., Davidson, M., Makdissi, A., Major, J., Febbraio, M., and Silverstein R.L. 2009. Lipid induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL. Obesity. 17(12):2142-8.
    • Klenotic, P., Febbraio, M., Van Meir, E.G., and Silverstein R.L. 2010. Histidine-rich glycoprotein modulates the anti-angiogenic effects of vasculostatin. Am. J. Path;176(4):2039-50.
    • Kennedy, D.J., Kuchibhotla, S., Silverstein, R.L., Morton, R.E., and M. Febbraio. (2010). CD36 Mediates a Pro-inflammatory Signaling Loop in Fat and Contributes to Insulin Resistance Cardiovascular Research. Dec. 16.
    • Li, W., Febbraio, M., Reddy, S.P., Yu, D.-Y., Yamamoto, M., and Silverstein R.L. 2010. CD36 participates in a signaling pathway that regulates reactive oxygen species formation by vascular smooth muscle cells. J. Clin. Invest. 120(11):3996-4006
    • Rahaman, S.O., Febbraio, M., Zhou, G., Swat, W., and Silverstein R.L. 2011. Vav proteins mediate a CD36-dependent pro-atherogenic macrophage phenotype. J. Biol. Chem; 286(9):7010-7017.
    • Ren, B., Hale, J., Srikanthan, S., and Silverstein R.L. 2011. Lysophosphatidic Acid Suppresses Endothelial Cell CD36 Expression and Promotes Angiogenesis via a PKD- 1 Dependent Signaling Pathway. Blood. 117(22):6036-45.
    • Chen, K., Li, W., Major, J., Febbraio, M., and Silverstein R.L. 2011. Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state.  Blood. 117(21):5744-50
    • Ghosh, A., Murugesan, G., Chen, K., Zhang, L., Wang, Q., Febbraio, M., Anselmo, R.M., Marchant, K., Barnard, J., and Silverstein R.L. 2011. Platelet CD36 surface expression levels affect functional responses to oxidized LDL and are associated with inheritance of specific genetic polymorphisms. Blood 117(23):6355-66.
    • Klenotic, P.A., Page, R.C., Misra, S., and Silverstein R.L. 2011. Expression, purification and structural characterization of functionally replete Thrombospondin-1 type 1 repeats in a bacterial expression system. Protein Expression and Purification 80(2):253-9
    • Rahaman, S. O., Zhou G., and Silverstein R.L. 2011. Vav GEF regulates CD36-mediated macrophage foam cell formation via calcium and dynamin-dependent processes. J. Biol. Chem. 286(41):36011-9
    • Huang, W., Febbraio, M., and Silverstein R.L. 2011. Macrophage CD9 co-localizes with CD36 and participates in CD36-dependent responses to oxidized low density lipoprotein. PLos One 6(12):e29092. Epub 2011 Dec 21.
    • Chu, L.-Y. and Silverstein R.L. 2012. CD36 ecto-domain phosphorylation blocks thrombospondin-1 binding: structure - function relationships and regulation by protein kinase C. Arteriosclerosis, Thrombosis and Vascular Biology. Jan 12. 
    • Park, Y.M., Kashyap, S., Major, J., and Silverstein R.L. 2012. Insulin promotes macrophage foam cell formation: Potential implications in diabetes-related atherosclerosis. Lab. Invest. 
    • Zhu,W., Li, W., and Silverstein, R.L. 2012. Advanced glycation end products induce a pro-thrombotic phenotype in mice via interaction with platelet CD36. Blood (in press).
    • Park, Y.M., Drazba, J.A., Egelhoff, T., Vasanji, A., Febbraio, M., and Silverstein R.L. 2012. Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion. Molecular Biology of the Cell (under revision)
    • Silverstein, R.L. and M. Febbraio. 2009. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Science Signaling 2, re3.
    • Silverstein, R.L. 2012. Teaching an old dog new tricks: potential anti–athero-thrombotic use for statins. J. Clin. Invest. 122(2):478-81
    • Hale, J.S., Li, M., Sinyuk, M., Jahnen-Dechent, W., Lathia, J.D., and Silverstein, R.L.  2012. Context Dependent Role of the CD36 – Thrombospondin - Histidine-Rich Glycoprotein Axis in Tumor Angiogenesis and Growth.  PLoS One. 7(7):e40033. Epub 2012 Jul 10.
    • Kennedy, D.J., Chen, Y., Huang, W., Viterna,J., Liu, J., Westfall, K., Tian, J., Bartlett, D.J., Tang, W.H.W., Xie, Z., Shapiro, J.I., and R.L. Silverstein.   2013.  CD36 and Na/K-ATPase-1 Form a Pro-inflammatory Signaling Loop in Kidney.  Hypertension; 61(1): 216-24.
    • Klenotic PA, Page RC, Li W, Amick J, Misra S, Silverstein RL.  Molecular basis of anti-angiogenic thrombospondin-1 type 1 repeat domain interactions with CD36.  Arteriosclerosis, Thrombosis and Vascular Biology 2013 July;33(7):1655-62 
    • Rahaman SO, Li W, Silverstein RL.  2013. Vav guanine nucleotide exchange factors regulate atherosclerotic lesion development in mice. Arteriosclerosis, Thrombosis and Vascular Biology  Sep;33(9):2053-7.
    • Chu L-Y, Ramakrishnan DP, Silverstein RL.   Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 toVEGFR2 complex in microvascular endothelial cells.  2013.  Blood 122(10):1822-32.
    • Zhao Y, Xiong Z, Lechner EJ, Chan Y, Zhang Y, Ross MA, Stolz DB, Rosengart MR, Pilewski J, Ray P, Ray A, Silverstein RL, Lee JS.  2013.  Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury.  Mucosal Immunol; 7(2):440-8. 
    • Brown GT, Narayanan P, Li W, Silverstein RL, McIntyre TM.  2013. Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop.  J. Immunology; 191(10):5196-203. 
    • Gupta N, Li W, Willard B, Silverstein RL, McIntyre T.  2014. Proteasome proteolysis supports stimulated platelet function and thrombosis. Arteriosclerosis, Thrombosis and Vascular Biology. 34(1):160-8.
    • Wang Y, Fang C, Gao H, Bilodeau ML, Zhang Z, Croce K, Liu S, Morooka T, Sakuma M, Nakajima K, Yoneda S, Shi C, Zidar D, Andre P, Stephens G, Silverstein RL, Hogg N, Schmaier AH, Simon DI. 2014.  Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis.   J Clin Invest 124(5):2160-71.
    • Srikanthan, S., Li, W., Silverstein, R.L., McIntyre, T.  2014.  Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36, and inhibits pro-atherothombotic cellular functions.  J. Thrombosis and Haemostasis 12(11):1906-17 
    • Li W, Gigante A, Martinez A, Perez-Perez M-J, Yue H, Hirano M, McIntyre T, Silverstein RL.  2014. Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ. Res. 115(12):997-1006. 
    • Chadwick, A.C., Holme, R.L., Chen, Y., Thomas, M.J., Silverstein, R.L., Pritchard, K.A. Jr., Sahoo, D. Acrolein-modified HDL impairs reverse cholesterol transport and promotes pathways that lead to atherogenesis. PLoS One 2015 Apr 7; 10(4):e0123138
    • Hajj-Ali RA, Major J, Langford C, Hoffman GS, Clark T, Zhang L, Sun Z, Silverstein RL The interface of inflammation and subclinical atherosclerosis in granulomatosis with polyangiitis (Wegener's): a preliminary study. Transl Res. 2015 Oct;166(4):3366-74
    • Chen Y, Kennedy DJ, Ramakrishnan DP, Yang M, Huang W, Li Z, Xie Z, Silverstein RL.  CD36 Mediates Macrophage Pro-Atherogenic Responses to Oxidized LDL by Recruiting Na/K-ATPase/Lyn Complex. Science Signaling 2015 Sep 8;8(393):ra91. doi: 10.1126/scisignal.aaa 9623.
    • Zhu, W., Gregory, J.C., Org, E., Buffa, J.A., Gupta, N., Wang, Z., Li, L., Fu, X, Wu, Y., Mehrabian, M., Sartor, R.B., McIntyre, T.M., Silverstein, R.L., Tang, W.H.W., DiDonato, J.A., Brown, J.M., Lusis, A.J., Hazen, S.L. Gut microbial choline metabolite TMAO enhances platelet hyperreactivity and thrombosis risk.  Cell 2016. Mar 24;165(1):111-24. 
    • Ramakrishnan, DP, Hajj-Ali, R, Chen, Y, Silverstein, RL.  Extracellular vesicles inhibit microvascular endothelial cell angiogenesic activities by activating a CD36 dependent signaling pathway. 2016.  Arteriosclerosis, Thrombosis and Vascular Biology. 2016; 36:534-544.
    • Ren, B., Best, B., Ramakrishnan, D.P., Walcott, B., Storz,P., Silverstein, R.L.  LPA/PKD-1-FoxO1 signaling axis mediates endothelial cell CD36 transcriptional repression and proangiogenic and proarteriogenic reprogramming.  Arteriosclerosis, Thrombosis and Vascular Biology. 2016; 36:1197-208. 
    • Yang M, Cooley BC, Li W, Chen Y, Vasquez-Vivar J, Scoggins NO, Cameron S, Morrell CN, Silverstein RL. Platelet CD36 Promotes Thrombosis by Activating Redox Sensor ERK5 in Hyperlipidemic Conditions.  Blood. 2017; 129(21):2917-2927
    • Chen Y, Huang W, Yang M, Xin G, Cui W, Xie Z, Silverstein RL  Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. Arterioscler Thromb Vasc Biol. 2017 Jun 15. [Epub ahead of print]
    • Silverstein, R.L. 2017.  Chapter 144: Atherothrombosis. In Hematology, 7th Edition: Basic Principles and Practice, By Ronald Hoffman, MD, Edward J. Benz, Jr., MD, Leslie E. Silberstein, MD, Helen Heslop, MD, Jeffrey I. Weitz, MD.  Elsevier Press
    • Silverstein, R.L. 2017. Linking Metabolic Dysfunction to Atherosclerosis via Activation of Macrophage CD36 Gene Transcription by Retinol Binding Protein 4.  Circulation 135:1355-56.
    • Silverstein, R.L. 2018. Oxidized lipid uptake by scavenger receptor CD36 modulates endothelial surface properties and may contribute to atherogenesis. Arterio. Thromb. Vasc. Biol. 38:4-5.
    • Chen, Y., Silverstein R.L. 2018 Platelet metabolism meets thrombosis.  Blood. 132(1!); 1089-1091.
    • Yang M, Kholmukhamedov A, Schulte ML, Cooley B, Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe S, Silverstein RL. Platelet CD36 signaling through ERK5 promotes Caspase-Dependent Procoagulant Activity and Enhances Fibrin Desposition in Vivo. Blood Advances. 2018 Nov 13;2(21):2848-2861.
    • Yue H, Febbraio M, Klenotic PA, Kennedy D, Yu Y, Chen S, Gohara AF, Li O, Kuang B, McIntyre TM, Silverstein RL, Li W. CD36 Enhances Vascular Smooth Muscle Cell Proliferation and Development of Neointimal Hyperplasia. Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):263-275.
    • Bain W, Olonisakin T, Yu M, Qu Y, Hulver M, Xiong Z, Li H, Pilewski J, Mallampalli RK, Nouraie SM, Ray A, Ray P, Cheng Z, Shanks RMQ, St. Croix C, Silverstein RS, Lee JS. Platelets inhibit apoptotic lung epithelial cell death and protect mice against infection-induced lung injury. Blood Advances. 2019 Feb 12;(3):432-445
    • Yang M, Silverstein RL. 2019. CD36 Signaling in Vascular Redox Stress. Free Radicol Biology and Medicine. 136:159-171.
    • Yang M, Silverstein RL. 2019. CD36 and ERK5 link dyslipidemia to apoptotic-like platelet procoagulant function. Curr Opin Hematol. 2019 Jun 28. [Epub ahead of print]
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