department of pharmacology

Alvin H. Schmaier, M.D.

Schmaier

Chief, Division of Hematology/Oncology
Professor of Medicine
Robert W. Kellermeyer Professor of Hematology/Oncology

Phone: (216) 368-1172
Fax: (216) 368-3014
E-mail: schmaier@case.edu
WRB2-130

Research

Dr. Schmaier’s major investigative work is on the vascular biology of the plasma kallikrein/kinin (KKS) and rennin angiotensin (RAS) systems.  The Schmaier laboratory recognized that the endothelial cell enzyme prolylcarboxypeptidase activates plasma prekallikrein when bound to high molecular weight kininogen (JBC 277:17962-17969, 2002, FEBS Lett 523:167, 2002; Blood 103:4554, 2004; Am J Physiol Heart & Circ Physiol 289:H2697, 2005).  This finding provides a physiologic mechanism on how the plasma kallikrein/kinin system (KKS) becomes activated.  Prolylcarboxypeptidase previously has only been known as the enzyme to degrade angiotensin II, the vasoactive peptide of the renin angiotensin system (RAS).  Current work on prolylcarboxypeptidase is examining the structure and function of the protein, its tissue and organ distribution, and its physiologic activities in animal models.  Additional investigations are examining how the plasma kallikrein/kinin system has an outside-in signaling system and its influence on cell growth and proliferation. 

Other activities in the Schmaier laboratory are investigating the influence of the plasma kallikrein/kinin and renin angiotensin systems on arterial thrombosis risk.  Recent work has recognized that the bradykinin B2 receptor knockout mouse is protected from induced arterial thrombosis (Blood.  108:192, 2006).  The mechanism(s) for the thromboprotection seen in these animals is independent of the plasma coagulation, fibrinolytic, and anticoagulation systems.  It is mediated by changes in levels in the receptors and biologic peptides of the plasma kallikrein/kinin and renin angiotensin systems and their influence on vascular biology.  Current investigations are examining the thrombosis risk profiles of the bradykinin B2 receptor, prolylcarboxypeptidase, plasma kininogen, angiotensinogen, and angiotensin receptor 2 knockout mice. 

Another major research effort in the Schmaier laboratory is work to develop a novel class of selective inhibitors of a-thrombin activation of platelets.  A class of agents named ThrombostatinsTM has been developed an active site inhibitor of a-thrombin and a thrombin receptor activation antagonist to protease activated receptors 1 and 4 (PAR 1and 4) (Chemical Biology & Drug Design.  68:235, 2006).  These compounds are based upon the angiotensin converting enzyme breakdown product of bradykinin, the peptide RPPGF.  Four proof-of-concept animal studies have been completed showing that this agent prevents coronary thrombosis in dogs and carotid thrombosis in mice.  Current investigations include further refining the mechanism by which RPPGF and Thrombostatins interfere with thrombin-mediated platelet activation (Biochemistry. 46:8603, 2007).  Current, investigations are characterizing the mechanisms of thrombin activation of PAR 1 and 4 on cells and how these receptors co-localize to regulate their activation as well as developing newer antagonists to PAR activation. 

 

Recent Major Publications:

Mahdi, F., Shariat-Madar, Z., Kuo, A., Carinato, M., Cines, D.B., Schmaier, A.H.  Mapping the interaction between high molecular weight kininogen and the urokinase plasminogen activator receptor.  J. Biol. Chem.  279:16621-16628, 2004.

Shariat-Madar, Z., Mahdi, F., Schmaier, A.H.  Recombinant prolylcarboxypeptidase activates plasma prekallikrein.  Blood.  103:4554-4561, 2004. 

Nieman, M.T., Warnock, M., Hasan, A.A.K., Mahdi, F., Lucchesi, B.R., Brown, N.J., Murphey, L.J., Schmaier,  A.H.  The preparation and characterization of novel peptide antagonists to thrombin, factor VIIa and activation of protease activated receptor1.  J Pharmacol Exp. Ther.  311:492-501, 2004.

Parker, A.C., Mundada, L.V., Schmaier, A.H., Fay, W.P.  Factor VLeiden inhibits fibrinolysis in vivo.  Circulation.  110:3594-3598, 2004.

Nieman, M.T., Pagan-Ramos, E., Warnock, M., Krijanovski, Y., Hasan, A.A.K., Schmaier, A.H.  Mapping the interaction of bradykinin 1-5 with the exodomain of protease activated receptor 4 (PAR4).  FEBS Lett.  579:25-29, 2005.

Zhou, L., Schmaier, A.H.  Platelet aggregation testing in platelet-rich plasma: description of procedures with the aim to develop standards in the field.  Amer J. Clin. Path.  123:172-183, 2005.

Shariat-Madar, Z., Rahimi, E., Mahdi, F., Schmaier, A.H.  Over-expression of prolylcarboxypeptidase enhances plasma prekallikrein activation on Chinese hamster ovary cell.  Am J Physiol Heart & Circ Physiol.  289:H2697- H2703, 2005.

Shariat-Madar, Z., Mahdi, F., Warnock, M., Homeister, J.W., Srikanth, S., Krijanovski, Y., Murphey, L.J., Jaffa, A.A., Schmaier, A.H.  Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin.  Blood.  108:192-199, 2006.

Burke, F.M., Warnock, M., Schmaier, A.H., Mosberg, M.I.  Synthesis of novel peptide inhibitors of thrombin-induced platelet activation.  Chemical Biology & Drug Design.  68:235-238, 2006.

Chen, X., Wang, J., Paszti, Z., Wang, F., Schrauben, J.N., Tarabara, V.V., Schmaier, A.H., Chen, Z.  Ordered adsorption of coagulation factor XII on negatively charged polymer surfaces by sum frequency generation vibrational spectroscopy.  Anal Bioanal Chem.  388:65-72, 2007.

Astern, J.M., Pendergraft, W.F. III, Falk, R.J., Jennetter J.C., Schmaier, A.H., Mahdi, F., Preston, G.A. Myeloperoxidase interacts with endothelial cell-surface cytokeratin 1 and modulates the plasma kallikrein kininogen system.  Amer J. Path.  171:349-360, 2007.

Wada, M., DeLong, C.J., Hong, Y., Rieke, C.J., Song, I., Sidhu, R.S., Warnock, M., Schmaier, A.H.,
Yokoyama, C., Smyth, E.M., Wilson, S.J., FitzGerald, G.A., Garavito, R.M., Sui, D., Regan, J.W., Smith, W.L.  Specificities of enzymes and receptors of prostaglandin pathways with arachidonic acid and eicosapentaenoic acid derived substrates and products.  J Biol. Chem.  282:22254-22266, 2007.

Nieman, M.T., Schmaier, A.H.  Interactions of thrombin with PAR1 and PAR4 at the thrombin
cleavage site.  Biochemistry.  46:8603-8610, 2007.