Roy L. Silverstein, MD

Roy L.  Roy L.  profile

Roy L. Silverstein, MD

Senior Investigator

Hemostasis, Thrombosis and Vascular Biology

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 Information
  • 414-955-0518
  • 414-955-0518
  • 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.

    • NIH – R01 HL142152: ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury
    • NIH – R01 HL153397: Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages

    Wenxin Huang, PhD
    Sr. Research Associate

    Mirza Ahmar Beg, PhD
    Postdoctorall Fellow

    Demetra Korkos
    Predoctoral Fellow

    Yiqiong Zhao
    Research Lab Technician

    Complete list of Published Work (217 papers in MyBibliography: H index = 72 (~20,000 citations)

    MyNCBI (Click Here)

    Selected Impactful and Recent Publications

    1. Xin G, Chen Y, Topchyan P, Kasmani M, Burns R, Volberding P, Cohn A, Chen Y, Lin CW, Ho PC, Silverstein RL, Dwinell M, Cui W. Targeting PIM1 Mediated Metabolism in Myeloid Suppressor Cells to Treat Cancer. Cancer Immunol Res. 2021 Apr;9(4):454-469. PMCID: PMC8137571
    2. Silverstein RL. Editorial on "PCSK9 Enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36”.  Circulation. 2021;143(1):62-64.
    3. Yang M, Li W, Harberg C, Chen W, Yue H, Ferreira RB, Wynia-Smith SL, Carroll KS, Zielonka J, Flaumenhaft R, Silverstein RL, Smith BC. Cysteine sulfenylation by CD36 signaling promotes arterial thrombosis in dyslipidemiaBlood Adv. 2020 Sep 22;(4)18:4494-4507. PMCID: PMC7509873
    4. Wang H, Franco F, Tsui Y-C, Xie X, Trefny MP, Zappasodi R, Mohmood SR, Fernández-García J, Tsai C-H, Schulze I, Picard F, Meylan E, Silverstein R, Goldberg I, Fendt S-M, Wolchok JD, Merghoub T, Jandus C, Zippelius A, Ho P-C. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumorsNat Immunol. 2020 Mar;21(3): 298-308. PMCID: PMC7043937
    5. Sodhi K, Denvir J, Liu J, Sanabria JR, Chen Y, Silverstein R, Xie ZJ, Abraham NG, Shapiro JI. Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification LoopInt J Mol Sci. 2020 Aug;21(16): E5923. PMCID: PMC7460641
    6. Chen Y, Yang M, Huang W, Chen W, Zhao Y, Schulte ML, Volberding P, Gerbec Z, Zimmermann MT, Zeighami A, Demos W, Zhang J, Knaack D, Smith BC, Cui W, Malarkannan S, Sodhi K, Shapiro JI, Xie J, Sahoo D, Silverstein RLMitochondrial metabolic reprogramming by CD36 signaling drives macrophage inflammatory responsesCirc Res. 2019; 125(12): 1087-1102. PMCID: PMC6921463
    7. Yang M, Silverstein RLCD36 Signaling in Vascular Redox Stress.  Free Radic Biol Med. 2019;136:159-171. PMCID: PMC6488418
    8. Chen Y, Silverstein RLPlatelet metabolism meets thrombosis.  Blood. 2018;132(11): 1089-1091. PMID: 30213838
    9. Yang M, Kholmukhamedov A, Schulte ML, Cooley B, Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe S, Silverstein RLPlatelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo.  Blood Adv. 2018;2(21):2848-2861. PMCID: PMC6234364 
    10. 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-ATPaseArterioscler Thromb Vasc Biol. 2017; 37(8):1462-1469. PMCID: PMC5532064
    11. Yang M, Cooley BC, Li W, Chen Y, Vasquez-Vivar J, Scoggins NO, Cameron S, Morrell CN, Silverstein RLPlatelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions. Blood. 2017;129(21): 2917-2927. PMCID: PMC5445574
    12. 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. Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis.  J Clin Invest 2014; 124(5):2160-71. PMCID: PMC4001535
    13. Li W, Gigante A, Perez-Perez MJ, Yue H, Hirano M, McIntyre TM, Silverstein RLThymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ Res. 2014; 115(12):997-1006. PMCID: PMC4258140
    14. Klenotic PA, Page RC, Li W, Amick J, Misra S, Silverstein RLMolecular basis of anti-angiogenic thrombospondin-1 type 1 repeat domain interactions with CD36Arterioscler Thromb Vasc Biol. 2013; 33(7):1655-62. PMCID: PMC3737738
    15. Zhu W, Li W, Silverstein RL.  Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood. 2012; 119(25):6136-44. PMCID: PMC3383021
    16. Chen K, Li W, Major J, Febbraio M, Silverstein RLVav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state.  Blood. 2011;117(21):5744-50. PMCID: PMC3110031
    17. Park YM, Febbraio M, Silverstein RLCD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intimaJ Clin Invest. 2009;119(1):136-145. PMCID: PMC2613464
    18. Silverstein RL, Febbraio M.  CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.  Sci Signal. 2009;2(72):re3. PMCID: PMC2811062
    19. Ghosh A, Li W, Febbraio M, Espinola RG, Cotrell E, McCrae K, Silverstein RL.  Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice.  J Clin Inv. 2008;118(5):1934-1943. PMCID: PMC2323190
    20. Chen K, Febbraio M, Li W, Silverstein RL.  A specific CD36-dependent signaling pathway is required for platelet activation by oxidized LDL.  Circ Res. 2008;102(12); 1512-1519. PMCID: PMC2749986
    21. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Valiyaveettil M, Poliakov E, Sun M, Finton PJ, Curtis BR, Chen J, Zhang R, Silverstein RL, Hazen SL. Platelet CD36 links hyperlipidemia, oxidant stress and a pro-thrombotic phenotypeNat Med. 2007;13(9):1086-1095. PMCID: PMC3042888
    22. Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RLCD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006;4(3):211-221. PMCID: PMC1855263
    23. Jiménez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck NP. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6(1): 41-48. PMID: 10613822
    24. Febbraio M, Podrez EA, Smith JD, Hazen SL, Hoff HF, Sharma K, Hajjar DP, Silverstein RLTargeted disruption of the class B scavenger receptor CD36 protects against athersclerotic lesion development in mice. J Clin Invest. 2000;105(8);1049-1056. PMCID: PMC300837
     
    Thrombosis & Hemostasis
    We study the properties of blood that cause it to clot. Our findings help to treat diseases that cause blood clots or excessive bleeding.
     
    Join Versiti Blood Research Institute
    Versiti Blood Research Institute, located in Milwaukee, Wisconsin, includes basic and clinical researchers in a variety of blood health fields.
     
    Our Experts
    Research investigators, postdoctoral fellows and laboratory staff at Versiti Blood Research Institute and Diagnostic Laboratories.
     
    Versiti Blood Research Institute
    Versiti Blood Research Institute investigators study blood disorders like hemophilia, blood cancers like leukemia, and other blood diseases.