Roy L. Silverstein, M.D.

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

Senior Investigator
Blood Research Institute
Blood Center of Wisconsin
Milwaukee, WI

Primary Research:
The goal of my research is to bridge bench to bedside to gain understanding of mechanisms responsible for athero-thrombotic and other vascular diseases, including angiogenesis. Our focus for nearly 25 years has been the vascular biology of the type B scavenger receptor CD36. We study this receptor on platelets, macrophages and microvascular endothelial cells using cell-based and mouse model systems and have explored cell signaling cascades triggered by the receptor, structure-function relationships responsible for its broad ligand specificity (e.g. for thrombospondin-related proteins and for oxidized phospholipids), and pathobiological processes related to thrombosis, atherosclerosis, inflammation and angiogenesis.

Lab Members:
Bin Ren, MD, PhD (research scientist and Assistant Professor, supported by AHA SDG)
Wenxin Huang, PhD (senior research associate)
Yiliang Chen, PhD (postdoctoral fellow, supported by AHA Fellowship)
Gabriella Kartz, PhD (postdoctoral fellow supported by cardiovascular T32)
Devi Prasadh Ramakrishnan (graduate student)
Moua Yang (graduate student)
Gloria Rong Yuan (research technician

Number of Trainee Members: 4 (2 PhD students and 2 postdocs)
We always have at least two students in the laboratory during the summer (one medical and one undergraduate)

Find more information on the web:
http://www.bcw.edu/bcw/Research/Investigators/ROY_SILVERSTEIN

Recent Publications:

Related to Angiogenesis/Vascular Biology:
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.

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.

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

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. 32(3):760-7. Epub Jan 12.

Ganesh SK, Tragante V, Guo W, ....., Silverstein RL, ...., Keating BJ, Asselbergs FW. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013. Apr 15;22(8):1663-78.

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.

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 Jun 21;119(25):6136-44. Epub March 19.

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

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.

Related to Platelet Biology and Thrombosis

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.

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.

Jankowska, A.M., Szpurka, H., Calabro, M., Mohan, S., Schade, A.E., Silverstein, R.L., and J.P. Maciejewski. 2011. Loss of expression of neutrophil proteinase-3 contributes to thrombotic risk in paroxysmal nocturnal hemoglobinuria. Hematologia. 96(7):954-62.

Timur, A.A., Murugesan, G., Zhang, L., Aungu, P.P., Barnard, J., Wang, Q.K., Gaussem, P., Silverstein, R.L., Bhatt, D.L., and K. Kottke-Marchant. 2012. P2RY1 and P2RY12 polymorphisms associated with on-aspirin platelet reactivity and atherothrombotic events in patients with coronary artery disease and percutaneous coronary intervention. Int. J. Laboratory Hematology. Epub May 10

Brown GT, Narayanan P, Li W, Silverstein RL, McIntyre TM. 2013. Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop. J. Immunology (Epub ahead of print Sept 30).

Gupta N, Li W, Willard B, Silverstein RL, McIntyre T. 2013. Proteasome proteolysis supports stimulated platelet function and thrombosis. Arteriosclerosis, Thrombosis and Vascular Biology. Oct 31 (Epub ahead of print)

Related to Athero-Inflammation

Lvovich V.F., Srikanthan S., Silverstein R.L. 2010. A novel broadband impedance method for detection of cell-derived microparticles. Biosens. Bioelectr. 26:444-451.

Kennedy, D.J., Kuchibhotla, S., Westfall K.M., Silverstein, R.L., Morton, R.E., and M. Febbraio. (2011). CD36 Mediates a Pro-inflammatory Signaling Loop in Fat and Contributes to Insulin Resistance Cardiovascular Research. 89(3):604-613.

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.

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

Smiechowski, M.F., Lvovich, V.F., Srikanthan, S., Silverstein, R.L. 2011. Non-linear impedance characterization of blood cells-derived microparticle biomarkers suspensions.
Electrochimica Acta 56(23): 7763 - 7771

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.

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. Aug; 92(8):1171-80.Epub April 23.

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 Aug;23(16):3057-3068. Epub 2012 Jun 20

Asselbergs FW, Guo Y, van Iperen EP, ..... Silverstein RL, .... Elbers CC, Keating BJ, Drenos F. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. Am J Hum Genet. 2012 Nov 2;91(5):823-38.

Guo Y, Lanktree MB, Taylor KC, Hakonsarson H, Lange LA, Keating BJ; The IBC 50K SNP array BMI Consortium. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. Hum Mol Genet. 2013; Jan 1;22(1):184-201.

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-a1 Form a Pro-inflammatory Signaling Loop in Kidney. Hypertension; 61(1): 216-24.

Zhou M-S, Chadipiralla K, Mendez AJ, Jaimes EA, Silverstein RL, Webster K, Raij L. Nicotine potentiates oxLDL-induced proatherogenic effects via stimulating and upregulating macrophage CD36 signaling. 2013. Am J Phys. – Heart and Circ. Phys. June 7 [Epub ahead of print]

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.

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 (Epub ahead of print Sept 18).

Collaborations:
We collaborate with Drs. Stan Hazen, Tom McIntyre and Wei Li at the Lerner Research Institute (Cleveland Clinic) and Dan Simon at Case Western Reserve (Cardiovascular Research Center). We also collaborate with Janet Lee at University of Pittsburgh and Dr. Brian Cooley at University of North Carolina.

Recent Presentations:

• National and Regional Meetings
  • American Society of Hematology National Meeting Scientific Program on Laboratory Medicine (12/11; San Diego) – "Platelet interactions with cell derived microparticles"
  • Gordon Research Conference on Hemostasis (7/12) – Platelet CD36 Mediates Prothrombotic Responses to Endogenous Danger Signals"
  • American Assoc of Blood Bankers (AABB) annual meeting (11/12; Boston): Platelet CD36 Mediates Prothrombotic Responses to Endogenous Danger Signals"
  • Midwest Platelet Conference 14th Biennial Meeting, (8/12; Cleveland). Platelet CD36 interactions with DAMPs promote thrombosis
• Other Presentations
  • Bin Ren. HDAC 7 Couples LPA Signaling to Endothelial Cell CD36 Gene Regulation to Switch off TSP-1 Mediated Antiangiogenic Responses, AHA Scientific Session Oral Presentation, Chicago, IL, 2010 (oral)
  • Bin Ren. Protein Kinase PKD-1 Signals HDAC7 to Regulate CD36 Transcription via FoxO1 in Endothelial Cells, NAVBO Cardiovascular Research Workshop Poster, Cape Cod, MA, 2011 (poster)
  • Bin Ren. A novel LPA-PKD-FoxO1 pathway in endothelial cells provides an angiogenic switch via down-regulation of CD36 transcription and induction of arteriogenic responses. American Association of Cancer Research (AACR) Annual Meeting April 6-10, 2013 (a late-breaking abstract poster).
  • Bin Ren. Protein Kinase D-1 Regulates CD36 Transcription and Arteriogenic Differentiation of Endothelial Cells. ATVB Annual Conference, Lake Buena Vista, FL, - May 1-3, 2013. (poster)
  • Yiliang Chen. 2012. ATVB meeting, poster presentation "CD36 mediates cholesterol uptake via Na/K-ATPase/Lyn signaling in macrophages". Because the poster was considered top 10% of accepted abstracts, he was invited to present the same poster again in 2012 AHA Scientific Session.