John Cleator, M.D., Ph.D.

Assistant Professor of Medicine

Research Description

The main focus is on defining the role of protease activated receptor regulation of platelet and vascular function and its impact on treating cardiovascular disease. Thrombin's effects on platelets, endothelial and vascular smooth muscle cells (VSMCs) are mediated primarily by activating protease activated receptor -1 (PAR-1). PAR-1 antagonists are currently being developed and tested as antiplatelet agents 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).

Another focus is examining the role of PARs in regulation of platelet function in patients treated with P2Y12 antagonists undergoing PCI. We have been studying platelet reactivity to thrombin through its receptors PAR1 and PAR4, and have found variability between normal and T2DM patients. In our published preliminary data, platelets from T2DM patients stimulated with thrombin show resistance to antagonism of P2Y12 receptors as compared to non-T2DM subjects 2. We have also observed variability between African American and Caucasian derived samples; samples from African American T2DM subjects do not exhibit this resistance, i.e. despite having T2DM; they are responsive to P2Y12 inhibition. Our published preliminary data derive from experiments in which a direct P2Y12 antagonist (2MEsAMP) was added ex vivo. We seek to determine if platelets from diabetic patients display resistance to oral P2Y12 receptor antagonists. The below are current ongoing projects in my laboratory:

1. Examining the in vivo role PAR-1 in a large animal model before and after inducing hypercholesterolemia and resultant endothelial dysfunction.
2. Determining if resistance to P2Y12 antagonists is altered platelets obtained from diabetic patients undergoing PCI.
3. Defining if PAR-1 single nucleotide polymorphisms are found in a BioVU subjects already identified to have recurrent ischemic events after PCI.

Selected Publications