Alvin H. Schmaier, M.D.
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.