Department of Internal Medicine

Hematology, Oncology and Blood &  Marrow Transplantation Faculty

Steven Lentz photo

Medical School:
Washington University

Graduate School:
Molecular Biology,
Washington University

Residency:
Barnes Hospital

Fellowship:
Washington University

Steven R. Lentz, M.D., Ph.D.
Professor and Division Director
Henry Hamilton Chair in Hematology
Director, Medical Scientist Training Program, Carver College of Medicine

In the clinic, Dr. Lentz cares for patients with hemostatic and hematological disorders.

The major focus of research in Dr. Lentz's laboratory is endothelial function in vascular diseases and tissue injury, with particular emphasis on structure, function, and regulation of hemostatic proteins. Dr. Lentz’s laboratory utilizes molecular and cellular techniques, along with transgenic and gene targeted animals, to investigate the mechanisms of regulation of hemostasis by vascular cells such as endothelium, vascular muscle, and platelets. The long-term goals of the laboratory are to define the molecular and cellular interactions that regulate vascular function and to identify the key mechanisms of impairment of vascular function in disease states such as hyperhomocysteinemia and atherosclerosis. Dr. Lentz also directs a clinical research program in hemophilia and thrombophilia and is a member of the Executive Committee of the the NCI-funded University of Iowa Lymphoma SPORE. Current areas of investigation include the following:

Vascular function in hyperhomocysteinemia and atherosclerosis.  A high blood level of the sulfur-containing amino acid, homocysteine, is a risk factor for cardiovascular disease, stroke, venous thromboembolism, and vascular dementia. This condition is called hyperhomocysteinemia. We are using molecular genetic approaches to define the mechanisms of vascular dysfunction and accelerated thrombosis in hyperhomocysteinemia. Current projects are investigating the role of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, and the signaling pathways that provide protection from cellular stress. We also use genetic approaches to investigate mechanisms of altered endothelial regulation of hemostatic function, including impairment of the thrombomodulin/protein C anticoagulant pathway during atherosclerosis and regression of atherosclerosis.

Platelet procoagulant activity.  We have developed methods to study platelet activation and the generation of platelet procoagulant activity in mice. We are currently are using genetic approaches in mice to further define the signal transduction pathways responsible for platelet procoagulant activity.
Hemophilia and thrombosis.  Under the direction of Dr. Lentz, the Iowa Hemophilia and Thrombosis Center conducts a broad program of clinical trials in hemophilia and venous thromboembolism.

Honors, Awards, and Organizations

Links of Interest

Recent Publications

  1. Lentz, S.R. and Sadler, J.E. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. (1991) J. Clin. Invest. 88:1906-1914.
  2. Raife, T.J., Lager, D.J., Madison, K.C., Piette, W.W., Howard, E.J., Sturm, M.T., Chen, Y. and Lentz, S.R. Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation. (1994) J. Clin. Invest. 93:1846-1851.
  3. Lentz, S.R., Sobey, C.G., Piegors, D.J., Bhopatkar, M.Y., Faraci, F.M., Malinow, M.R., and Heistad, D.D. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. (1996) J. Clin. Invest. 98:24-29.
  4. Raife, T.J., Demetroulis, E.M., and Lentz, S.R. Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-a: differential responses in keratinocytes and endothelial cells. (1996) Blood 88:2043-2049.
  5. Joyce, D.E., Chen, Y., Erger, R.A., Koretzky, G.A., and Lentz, S.R. Functional interactions between the thrombin receptor and the T cell antigen receptor in human T cell lines. (1997) Blood 90:1893-1901.
  6. Lentz, S.R., Malinow, M.R., Piegors, D.J., Bhopatkar-Teredesai, M., Faraci, F.M., and Heistad, D.D. Consequences of hyperhomocyst(e)inemia on vascular function in atherosclerotic monkeys. (1997) Arterioscler. Thromb. Vasc. Biol. 17:2930-2934.
  7. Clements, J.L., Lee, J.R., Yang, B., Olson, J.D., Sandra, A., Lentz, S.R., and Koretzky,G.A. Fetal hemorrhage and platelet dysfunction in SLP-76 deficient mice. J. Clin. Invest. (1999) 103:19-25.
  8. Lentz, S.R., Fernandez, J.A., Griffin, J.H., Piegors, D.J., Erger, R.A., J.A., Malinow, M.R., and Heistad, D.D. Impaired anticoagulant response to infusion of thrombin in atherosclerotic monkeys associated with acquired defects in the protein C system. Arteroscler. Thromb. Vasc. Biol. (1999) 19:1744-1750.
  9. Peterson, J.J., Rayburn, H.B., Lager, D.J., Raife, T.J., Kealey, G.P., Rosenberg, R.D., and Lentz, S.R. Expression of thrombomodulin and consequences of thrombomodulin deficiency during healing of cutaneous wounds. Am. J. Pathol. (1999) 155:1569-1575.
  10. Böger, R.H., Bode-Böger, S.M., Heistad, D.D., Frolich, J.C. and Lentz, S.R. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia. Arterioscler. Thromb. Vasc. Biol. (2000) 20:1557-1564.
  11. Lentz, S.R., Erger, R.A., Dayal, S., Maeda, N., Malinow, M.R., Heistad, D.D., and Faraci, F.M. Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine b-synthase-deficient mice. Am. J. Physiol. (2000) 279:H970-H975.
  12. Böger, R.H., Lentz, S.R., Bode-Böger, S.M., Knapp, H.R., and Haynes, W.G. Elevation of asymmetric dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inemia in humans. Clin. Sci. (2001) 100:161-167.
  13. Lentz, S. R. Piegors, D.J., Malinow, M.R., and Heistad, D.D. Supplementation of atherogenic diet with B vitamins does not prevent atherosclerosis or vascular dysfunction in monkeys. Circulation (2001) 103:1006-1011.
  14. Werstuck, G.H., Lentz, S.R., Dayal, S., Hossain, G.S., Sood, S.K., Shi, Y.Y., Zhou, J., Maeda, N., Malinow, M.R., Krisans, S.K., Malinow, M.R., and Austin, R.C. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and fatty acid biosynthesis pathways. J. Clin. Invest. (2001) 107:1263-1273.
  15. Dayal, S., Bottiglieri, T., Arning, E., Maeda, N., Malinow, M.R., Sigmund, C.D., Heistad, D.D., Faraci, F.M., and Lentz, S.R. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine b-synthase-deficient mice. Circ. Res. (2001) 88:1203-1209.
  16. Lentz, S.R. Does homocysteine promote atherosclerosis? Arterioscler. Thromb. Vasc. Biol. (2001) 21:1385-1386.
  17. Raife, T.J., Lentz, S.R., Atkinson, B., Vesely, S.K., and Hessner, M.J. Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor-cleaving protease activity. Blood (2002) 99:437-442.
  18. Lentz, S.R., Miller, F.J., Jr., Piegors, D.J., Erger, R.A., Fernández, J.A., Griffin, J.H., and Heistad, D.D. Anticoagulant responses to thrombin are enhanced during regression of atherosclerosis in monkeys. Circulation (2002) 106:842-846.
  19. Lentz, S.R., Piegors, D.J., Fernández, J.A., Erger, R.A., Arning, E., Malinow, M.R., Griffin, J.H., Bottiglieri, T., Haynes, W.G., and Heistad, D.D. Effect of hyperhomocysteinemia on protein C activation and activity. Blood (2002) 100:2108-2112.
  20. Leo, L., Di Paola, J., Judd, B.A., Koretzky, G.A., and Lentz, S.R. Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen. Blood (2002) 100:2839-2844.
  21. Baumbach, G.L., Sigmund, C.D., Bottiglieri, T., and Lentz, S.R. Structure of cerebral arterioles in cystathionine b-synthase-deficient mice. Circ. Res. (2002) 91:931-937
  22. Dayal, S., Brown, K.L, Weydert, C.J., Oberley, L.W., Arling, E., Bottiglieri, T., Faraci, F.M., and Lentz, S.R. Deficiency of glutathione peroxidase-1 sensitizes to endothelial dysfunction in hyperhomocysteinemic mice. Arterioscler. Thromb. Vasc. Biol. (2002) 22:1996-2002.
  23. Slungaard, A., Fernández, J.A., Griffin, J.H., Key, N.L., Long, J.L., Piegors, D.J., and Lentz, S.R. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo. Blood (2003) 102:146-151.
  24. Elzey, B.D., Tian, J., Jensen, R.J., Swanson, A.K., Lees, J.R., Lentz, S.R., Stein, C., Nieswandt, B., Wang, Y., Davidson, B., and Ratliff, T.L. Platelet-mediated modulation of adaptive immunity: a communication link between innate and adaptive immune compartments. Immunity (2003) 19:9-19.
  25. Wilson, K.M., Lynch, C.M., Faraci, F.M., and Lentz, S.R. Effect of mechanical ventilation on carotid artery thrombosis induced by photochemical injury in mice. J. Thromb. Haemost. (2003) 1:2669-2674.
  26. Devlin, A.M., Arning, E., Bottiglieri, T., Faraci, F.M., Rozen, R., and Lentz, S.R. Effect of MTHFR genotype on diet-induced hyperhomocysteinemia and vascular dysfunction in mice. Blood (2004) 103:2624-2629.
  27. Zhou, J., Werstuck, G.H., Lhoták, Š., de Koning, A.B.L., Sood, S.K., Hossain, G.S., Møller, J., Ritskes-Hoitinga, M., Falk, E., Dayal, S., Lentz, S.R., and Austin, R.C. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apoE-deficient mice. Circulation (2004) 110:207-213.
  28. Dayal, S., Arning, E., Bottiglieri, T., Böger, R.H., Sigmund, C.D., Faraci, F.M., and Lentz, S.R. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke (2004) 35:1957-1962.
  29. Dayal, S., Devlin, A.M., McCaw, R.B., Liu, M.L., Arning, E., Bottiglieri, T., Shane, B., Faraci, F.M., and Lentz, S.R. Cerebral vascular dysfunction in methionine synthase-deficient mice. Circulation (2005) 112:737-744.
  30. Devlin, A.M., Bottiglieri, T., Domann, F.E., and Lentz, S.R. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. J. Biol. Chem. (2005) 280:25506-25511.
  31. Jobe, S.M., Leo, L., Eastvold, J., Dickneite, G., Ratliff, T.L., Lentz, S.R., and Di Paola, J. Role of FcRγ and factor XIIIA in coated platelet formation. Blood (2005) 106:4146-4151
    Lentz, S.R. Another lesson from the factor V Leiden mouse: thrombin generation drives arterial disease. Circulation (2005) 111:1733-1734.
  32. Lentz, S.R. Mechanisms of homocysteine-induced atherothrombosis. J. Thromb. Haemost. (2005) 3:1646-1654.
  33. Raife, T.J. and Lentz, S.R. The benefits of excess EPCR. J. Thromb. Haemost. (2005) 3:1349-1350.
  34. Devlin, A.M. and Lentz, S.R. Apo A-I: a missing link between homocysteine and lipid metabolism? Circ. Res. (2006) 98:431-433.
  35. Dayal, S., Wilson, K.M., Leo, L., Arning, E., Bottiglieri, T., and Lentz, S.R. Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood (2006) 108:2237-2243.
  36. Tsimikas,S., Aikawa,M., Miller, F.J., Jr., Miller, E.R., Torzewski,M., Lentz, S.R., Heistad, D.D., Libby, P., and Witzum, J.L. Increased plasma oxidized phospholipid:apolipoprotein B-100 ratio with concomitant depletion of oxidized phospholipids from atherosclerotic lesions following dietary lipid lowering: a potential biomarker of early atherosclerosis regression. Arterioscl. Thromb. Vasc. Biol. (2007) 27:175-181.
  37. Wilson, K.M., McCaw, R.B., Leo, L., Arning, E., Lhoták, Š., Bottiglieri, Austin, R.C., and Lentz, S.R. Prothrombotic effects of hypercholesterolemia and hyperhomocysteinemia in ApoE-deficient mice. Arterioscl. Thromb. Vasc. Biol. (2007) 27:233-240.
  38. Sontag, E., Nunbhakdi-Craig, V., Sontag, J.M., Diaz-Arrastia, R., Ogris, E., Dayal, S., Lentz, S.R., Arning, E, and Bottiglieri, T. PP2A methyltransferase links homocysteine metabolism with tau and APP regulation. J. Neurosci. (2007) 27:2751-2759.
  39. Kitayama, J., Faraci, F.M., Lentz, S.R., and Heistad, D.D. Cerebral vascular dysfunction during hypercholesterolemia. Stroke (2007) 38:2136-2141.
  40. Devlin, A.M., Boersma, H.M., Wade, R.E., Singh, R., Innis, S.M., Bottiglieri, T., and Lentz, S.R. Reduced methylation capacity in mice with hyperhomocysteinemia is associated with altered hepatic fatty acid and phospholipid metabolism. J. Biol. Chem. (2007) 282:37082-37090.
  41. Dayoub H., Rodionov, R.N., Lynch, C., Cooke, J.P., Arning, E., Bottiglieri, T., Lentz, S.R., and Faraci, F.M. Overexpression of dimethylarginine dimethylaminohydrolase inhibits ADMA-induced endothelial dysfunction in cerebral circulation. Stroke (2008) 39:180-184.
  42. Jobe, S.M., Wilson, K.M., Leo, L., Raimondi, A., Molkentin, J.D., Lentz, S.R., and Di Paola, J. Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation. Blood (2008) 111:1257-1265 [PMCID: PMC2214770].
  43. Rodionov, R.N. and Lentz, S.R. The homocysteine paradox. Arterioscl. Thromb. Vasc. Biol. (2008) 28:1031-1033 [PMCID: PMC2430733].
  44. Chrissobolis, S., Didion, S.P., Kinzenbaw, D.A., Schrader, L.I., Dayal, S., Lentz, S.R., and Faraci, F.M. Glutathione peroxidase-1 plays a major role in protecting against angiotensin II-induced vascular dysfunction. Hypertension (2008) 51:872-877.
  45. Dayal, S. and Lentz, S.R. Murine models of hyperhomocysteinemia and their vascular phenotypes. Arterioscler. Thromb. Vasc. Biol. (2008) 28:1596-1605 [PMCID: PMC2574668].
  46. Dayal, S., Rodionov, R.N., Arning, E., Bottiglieri, T., Kimoto, M., Murry, D.J., Faraci, F.M., and Lentz, S.R. Tissue specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia. Am. J. Physiol. Heart Circ. Physiol. (2008) 295:H816-H825. [PMCID PMC2519228].
  47. Modrick, M.L., Didion, S.P., Lynch, C.M., Dayal, S., Lentz, S.R., and Faraci, F.M. Role of hydrogen peroxide and the impact of glutathione peroxidase-1 in regulation of vascular tone. J. Cereb. Blood Flow Metab. (2009) 29:1130-1137.
  48. Raife, T.J., Cao, W., Atkinson, B.S., Bedell, B., Montgomery, R.R., Lentz, S.R., Johnson, G.F. and Zheng, X.L., Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood (2009) 114:1666-1674.
  49. Stevens, J.W. and Lentz, S.R. Countervailing effects on atherogenesis and plaque stability: a paradoxical benefit of hypercoagulability? Circulation (2009) 120:722-724.

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