Alvin H. Schmaier, MD

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.