Eugene Podrez Laboratory

Research

The major focus of our lab is how inflammation and oxidative stress contribute to atherosclerosis and thrombosis via lipid peroxidation and formation of bioactive lipids. Specifically, we are interested in how these conditions induce platelet “hyper-reactivity” associated with dislipoproteinemia, which is a known contributor to arterial thrombosis and plays an important role in atherosclerotic lesion formation. We are testing the hypothesis that platelets are activated in vivo by a recently discovered family of novel oxidized phospholipids. We have found that platelet scavenger receptors type B serve as sensors of specific oxidized phospholipids in plasma and mediate increased platelet reactivity in conditions of oxidative stress. This recognition leads to platelet activation and prothrombogenic status observed in hyperlipidemia, and may also account for platelet interactions with monocytes and endothelial cells in the initial stages of atherosclerosis development. Our research suggests that scavenger receptors type B on platelets may be the target for new therapies to reduce the risk of life-threatening events. 

Our lab is also working towards elucidating the mechanisms of impairment of cholesterol efflux in cells in atherosclerosis. We have found that products of lipid oxidation may not only promote uptake of modified lipoproteins by macrophages via scavenger receptors, but these products can also interfere with cellular cholesterol efflux machinery and induce intracellular cholesterol accumulation by compromising cholesterol efflux.

Selected Publications

View publications for Eugene Podrez, MD, PhD
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1. Panigrahi S, Ma Y, Hong L, Gao G, West XZ, Salomon RG, Byzova TV, and Podrez EA: Engagement of platelet Toll-like receptor 9 by novel endogenous ligands promotes platelet hyper-reactivity and thrombosis. Circulation Research, v. 112(1), p. 103-12. 2013.
2. Ling L, Biswas S, Morton RE, Smith JD, Hay N, Byzova T, Febbraio M, and Podrez EA: Akt3 Deficiency in Macrophages Promotes Foam Cell Formation and Atherosclerosis in Mice. Cell Metabolism, v. 15. p 861-872. 2012.
3. Ding L, Biswas S, Morton RE, Smith JD, Hay N, Byzova T, Febbraio M, and Podrez EA: Akt3 Deficiency in Macrophages Promotes Foam Cell Formation and Atherosclerosis in Mice. Cell Metabolism, v. 15. p 861-872. 2012.
4. Ma Y, Ashraf Z, and Podrez E.A: Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia. Blood, v. 116(11). p 1932-41. 2010.
5. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Poliakov E, Valiyaveettil M, Sun M, Curtis BR, Finton PJ, Chen J, Zhang R, Silverstein RL, and Hazen SL: CD36 links hyperlipidemia, oxidant stress and a pro-thrombotic phenotype. Nature Medicine, v. 13(9). p 1086-95. 2007.

ADDITIONAL PUBLICATIONS

1. Gao D and Podrez EA: Analysis of relationships between oxidized phospholipid structure and interaction with the class B scavenger receptors. Advanced Protocols in Oxidative Stress II, Methods in Molecular Biology, 2014, Humana Press.
2. Gao D, Willard B, Podrez EA: Analysis of covalent modifications of proteins by oxidized phospholipids using a novel method of peptide enrichment. Analytical Chemistry, v. 86(2). p1254-62. 2014.
3. Zimman A, Biswas S, Titz B, Komisopoulou E, Graeber TG, and Podrez EA: Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin.  PLoS One, v. 9(1):e84488. 2014.
4. Podrez EA: Bad vs good cholesterol in the bone marrow. Nature Medicine, v.19. p 541-542. 2013.
5. Kerr BA, Lining M, West XZ, Malinin NL, Weber ME, Ding L, Somanath PR, Penn MS, Podrez EA, and Byzova TV: Interference with Akt signaling protects against myocardial infarction and death by limiting the consequences of oxidative stress. Science Signaling, v. 6(287):ra67. 2013.
6. Panigrahi S, Ma Y, Hong L, Gao G, West XZ, Salomon RG, Byzova TV, and Podrez EA: Engagement of platelet Toll-like receptor 9 by novel endogenous ligands promotes platelet hyper-reactivity and thrombosis. Circulation Research, v. 112(1). p 103-12. 2013.
7. Pluskota E, Ma Y, Bialkowska K, Soloviev DA, Szpak D, Nestor C, Podrez EA, Golden JA, and Plow EF: Kindlin-2 Regulates Hemostasis by Controlling Endothelial Cell Surface Expression of ADP/AMP Catabolic Enzymes via a Clathrin-Dependent Mechanism. Blood, v. 122(14). p 2491-9. 2013.
8. Angheloiu G, van de Poll S, Georgakoudi I, Motz J, Haka A, Podrez EA, Fitzmaurice M, Feld M, Dasari LL, and Kramer J: Intrinsic versus laser-induced fluorescence spectroscopy for coronary atherosclerosis diagnosis: a generational comparison model for testing diagnostic accuracy. Applied Spectroscopy, v. 66. p 1403-1410. 2012.
9. Zhao Y, Malinin NL, Meller J, Ma Y, West XZ, Qin J, Podrez EA, and Byzova TV: Regulation of Cell Adhesion and Migration by Kindlin-3 Cleavage by Calpain. J Biol Chem, v. 287(47). p 40012-20. 2012.
10. Meller J, Malinin N, Panigrahi S, Kerr B, Patil A, Ma Y, Venkateswaran L, Rogozin Y, Narla M, Ehlayel M, Podrez EA, Chinen J, and Byzova TV: Novel aspects of Kindlin-3 function in humans based on a new case of Leukocyte Adhesion Deficiency III (LAD-III). Journal of Thrombosis and Haemostasis, v. 10(7). p 1397-1408. 2012.
11. Zimman A and Podrez EA: Regulation of platelet function by class B scavenger receptors in hyperlipidemia. Arteriosclerosis, Thrombosis and Vascular Biology, v. 30. p 2350-56. 2010.
12. Somanath PR, Podrez EA, Chen J, Ma Y, Antoch M, and Byzova TV: Deficiency in core circadian protein BMAL1 is associated with a prothrombotic and vascular phenotype. J Cell Physiol, v. 226(1). p 132-40. 2010.
13. Podrez EA: Anti-oxidant properties of high-density lipoprotein and atherosclerosis. Clinical and Experimental Pharmacology and Physiology, v. 37(7). p 719-25. 2010.
14. Zhang X, Malinin NL, Merkulova AA, M.Tischenko, Podrez EA, Salomon RG and Byzova TV: Oxidative stress induces angiogenesis by activation of TLR2 with novel endogenous ligands. Nature, v. 467(7318). p 972-6. 2010.
15. Ma Y, Ashraf Z, and Podrez EA: Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia. Blood, v. 116(11). p 1932-41. 2010.
16. Gao D, Ashraf MZ, Lin D, Sayre L, and Podrez EA: Structural basis for the recognition of oxidized phospholipids in oxidized low density lipoproteins by scavenger receptors class B CD36 and SR-BI. J Biol Chem, v. 285(7). p 4447-54. 2010.
17. Valiyaveettil M, and Podrez EA: Platelet hyperreactivity, scavenger receptors and athero-thrombosis. Journal of Thrombosis and Haemostasis, v. Jul;7 Suppl 1. p 218-21. 2009. 
18. Ashraf MZ, KarNS, and Podrez EA: Oxidized Phospholipids: Biomarker for Cardiovascular Diseases. International Journal of Biochemistry & Cell Biology, v. 41(6). p 1241-44. 2009.
19. Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma Y, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow E, and TV Byzova: A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nature Medicine, v. 15(3). p 313-8. 2009.
20. Valiyaveettil M, Kar N, Ashraf MZ, Byzova TV, Febbraio M, and Podrez EA: Oxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI. Blood, v. 111. p 1962-1971. 2008.
21. Ashraf MZ, Kar N, Salomon RG, Febbraio M, and Podrez EA: Specific Oxidized Phospholipids Inhibit Scavenger Receptor BI SR-BI Mediated Selective Uptake of Cholesteryl Esters. J Biol Chem, v. 283(16). p 10408-14. 2008.
22. KarNS, AshrafAZ, Valiyaveettil M, and Podrez EA: Mapping and Characterization of Binding Site for Specific Oxidized Phospholipids and Oxidized Low-Density Lipoprotein of Scavenger Receptor CD36. J Biol Chem, v. 283(13). p 8765-71. 2008.
23. Valiyaveettil M, Kar N, Ashraf MZ, Byzova TV, Febbraio M, and Podrez EAOxidized high-density lipoprotein inhibits platelet activation and aggregation via scavenger receptor BI. Blood, v. 111. p 1962-1971. 2008.
24. Ashraf MZ, Reddy MK, Hussain ME, Podrez EA, and Fahim M: Contribution of EDRF and EDHF to restoration of endothelial function following dietary restrictions in hypercholesterolemic rats. Indian J Exp Biol, v. 45(6). p 505-14. 2007.
25. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Poliakov E, Valiyaveettil M, Sun M, Curtis BR, Finton PJ, Chen J, Zhang R, Silverstein RL, and Hazen SL: CD36 links hyperlipidemia, oxidant stress and a pro-thrombotic phenotype. Nature Medicine, v. 13(9). p 1086-95. 2007.
26. Agrawal S, Xu B, Podrez EA, DiCorleto PE, Cathcart MK, Stark GR, and Chisolm GM: Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development. Circulation, v. 115(23). p 2939-47. 2007.
27. Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, and Silverstein RL: A CD36 dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metabolism, v. 4(3). p 211-221. 2006.
28. Angheloiu GO, Arendt JT, Müller MJ, Georgakoudi I, Haka AS, Motz JT, Kuban BD, Myles J, Miller F, Podrez EA, Feld MS, and Kramer JR: Intrinsic fluorescence and diffuse reflectance spectroscopy identify superficial foam cells in coronary plaques prone to erosion. Arterioscler Thromb Vasc Biol, v. 26(7). p 1594-600. 2006.
29. Sun M, FinnemannSC, Febbraio M, Shan L, Annangudi SP, Podrez EA, Hoppe G, Darrow R, Organisciak DT, Salomon RG, Silverstein RL and Hazen SL: Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium. J Biol Chem, v. 281(7). p 4222-30. 2005.
30. Narizhneva NV, Podrez EA, Chen J, Chandraesekharan U, DiCorleto PE, Plow EF, Topol EJ and Byzova TV: Thrombospondin-1 upregulates expression of cell adhesion molecules and promotes monocyte binding to endothelium. FASEB J, v. 19(9). p 1158-60. 2005.
31. Podrez EA, Hoppe G, and Hoff HF: Phospholipids in oxidized LDL not adducted to apo B are recognized by the CD36. Free Radic Biol Med, v. 34(3). p 356-64. 2003.
32. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee S, Silverstein RL, Hoff HF, and Freeman MW: SR Class A-I/II and CD36 are the principal modified lipoprotein uptake receptors in macrophages. J Biol Chem, v. 277. p 49982-88. 2002.
33. Podrez EA, Polyakov E, Shen Z, Zang R, Sun M, Febbraio M, Hajjar DP, Silverstein RL, Henry FH, Salomon RG, and Hazen SL: A novel family of atherogenic oxidized phospholipids induces macrophage foam cell formation via the scavenger receptor CD36 and is present in atherosclerotic lesions. J Biol Chem, v. 277. p 38517-38523. 2002.
34. Podrez EA, Polyakov E, Shen Z, Zang R, Deng Y, Sun M, Shen L, Gugiu B, Salomon RG, Hoff HF, and Hazen SL: Identification of structurally specific oxidized phospholipids as ligands for the macrophage scavenger receptor CD36. J Biol Chem, v. 277. p 38503-16. 2002.
35. Podrez EA, Hoppe G, O'Neil J, Sayre LM, Sheibani N, and Hoff HF: Macrophage receptors responsible for distinct recognition of LDL containing pyrrole or pyridinium adducts: models of oxidized LDL. J Lipid Res, v. 41. p 1455-1463. 2000.
36. Salomon RG, Kaur K, Podrez EA, Hoff HF, Krushinsky AV, and Sayre LM: HNE-derived pentylpyrroles are generated during oxidation of LDL, are prevalent in blood plasma from patients with renal disease or atherosclerosis, and are present in atherosclerotic plaques. Chem Res Toxicol, v. 13. p 557-564. 2000.
37. Podrez EA, Abu-Soud HM, and Hazen SL: Myeloperoxidase and oxidative modification of LDL. Free Rad Biol & Med, v. 28. p 1717-1725. 2000.
38. Salomon RG, Batyreva E, Kaur K, Crabb J, Penn MC, DiCorletoPE, Hazen SL, and Podrez EA: Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway. Biochimica et Biophysica Acta, v. 55616. p 1-11. 2000.
39. Febbraio M., Podrez EA, Smith JD, Hazen SL, Hoff HF, Sharma K, Hajjar DP, and Silverstein RL: Targeted disruption of the class B scavenger receptor, CD36, protects against atherosclerotic lesion development in mice. J Clin Invest, v. 105. p 1049-1056. 2000.
40. Podrez EA, Febbraio M, Sheibani N, Schmitt D, Silverstein RL, Hajjar DP, Frazier WA, Cohen P, Hoff HF, and Hazen SL:  The macrophage scavenger receptor CD36 is the major pathway for LDL recognition following modification by monocyte-generated reactive nitrogen species. J Clin Invest, v. 105. p 1095-1108. 2000.
41. Hazen SL, Zhang R, Shen Z, Wu W, Podrez EA, MacPherson JC, Schmitt D, Mitra SN, Mukhopadhyay C, Chen Y, Cohen PA, Hoff HF, and Abu-Soud HM: Formation of nitric oxide-derived oxidants by myeloperoxidase in monocytes: Pathways for monocyte-mediated protein nitration and lipid peroxidation in vivo. Circ Res, v. 85 (10). p 950-958. 1999.
42. Podrez EA, Schmidt D, Hoff HF and Hazen SL: Myeloperoxidase-H2O2-NO2- system of monocytes converts LDL into a form which promotes macrophage cholesterol accumulation and foam cell formation in vitro. J Clin Invest, v. 103(11). p 1547-1560. 1999.
43. Podrez EA, O'Neil J, Salomon RG, Schreiber MJ, and Hoff HF: Measurement of oxidation in plasma Lp(a) in CAPD patients using a novel ELISA. Kidney Int, v. 54(2). p 637-645. 1998.