Division of Cardiovascular Medicine
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Our lab is currently interested in understanding effects of activating the G-protein coupled Protease Activated Receptors in both in vivo large animal experiments as well as on the molecular levels in platelets and endothelial cells. Thrombin's effects on platelets, endothelial and vascular smooth muscle cells (VSMCs) are mediated primarily by activating the G protein coupled receptor, protease activated receptor-1 (PAR-1). PAR-1 antagonists are currently being developed and tested as an antiplatelet agent given during percutaneous coronary intervention (PCI) to prevent adverse events including myocardial infarction. Antagonizing the effects of PAR-1 on endothelium and vascular smooth muscle cells are largely unknown and could lead to further adverse events in certain clinical situations.
For example, in vivo studies reveal that PAR-1 mediates endothelium-independent vasodilatation in the human forearm. If one extrapolates this to the coronary vasculature, blocking potential PAR-1 mediated coronary vasodilatation during PCI might lead to increased adverse events involving the microcirculation ("coronary no reflow").
1. One current project is examining the in vivo role PAR-1 in large animal models before and after inducing hypercholesterolemia and resultant endothelial dysfunction.
2. A second related project seeks to understand why PAR-1 does not initiate intracellular signaling in large animal platelets despite being present on the plasma membrane.
3. Another project seeks to examine the role of PAR-1 in ex vivo isolated human coronary arteries (both in normal and diseased arteries) obtained from explanted hearts obtained from patients undergoing heart transplantation at Vanderbilt University.
4. Another focus is on determining if PAR-1 single nucleotide polymorphisms are found in BioVU subjects already identified to have recurrent ischemic events after percutaneous coronary intervention (PCI) here at VUMC. A related project is the establishment of a clinical and DNA database of patients presenting with STEMI and Out-of-hospital primary cardiac arrest (The ARREST study).