There is a growing body of evidence showing that the interaction between platelets and endothelial cells contributes significantly to the pathogenesis of atherosclerosis. Platelet adhesion to the inflamed endothelium triggers the formation of thrombi leading to atherosclerotic lesions. Furthermore, platelets are known to play a critical role in the acute exacerbations of chronic atherosclerotic disease, such as unstable angina and myocardial infarction, as well as in the thrombotic complications of percutaneous coronary intervention. A key molecule identified recently as critical for platelet adhesion to a thrombogenic endothelial surface is the F11 receptor (F11R). F11R is a novel cell adhesion molecule, a member of the immunoglobulin superfamily, and a human ortholog of a murine cell adhesion molecule found in endothelial cells termed Junctional Adhesion Molecule (JAM). It has been demonstrated that F11R plays a critical role in the adhesion of platelets to cytokine-inflamed endothelial cells, accounting for approximately 40% of this adhesiveness in normal controls. In addition, studies conducted at the applicant's institution have shown that F11R expression is increased in atherosclerotic plaques in an animal model of atherosclerosis, the apoE knock-out mouse. The human gene for F11R has recently been identified, sequenced and cloned. Furthermore, our laboratory has recently developed a sensitive ELISA to measure levels of soluble F11R in the plasma or sera of patients. Using this novel ELISA, we have shown that plasma F11R is independently associated with the presence and severity of angiographically- defined coronary artery disease. The objectives of this proposal are to examine the hypotheses that 1) the baseline plasma levels of F11R in patients with known or suspected CAD referred for coronary angiography are independent predictors of the development of long-term adverse cardiovascular outcomes, and 2) the baseline plasma levels of F11R in patients undergoing percutaneous coronary intervention are independent predictors of both short- and intermediate-term outcomes. The project, which is based on recent findings in basic science research, represents the first clinical investigation of F11R as a prognostic biomarker in patients with coronary artery disease.
This proposal will expand our preliminary work demonstrating a critical role for F11R in atherosclerosis and inflammatory thrombosis. The current proposal represents the first study in humans to examine the prognostic significance of baseline plasma F11R levels in patients with known or suspected coronary artery disease. It is expected that this work will contribute substantially to the biomarker field and lead to improvements in methods of cardiovascular risk stratification.
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|Cavusoglu, Erdal; Marmur, Jonathan D; Hegde, Sudhanva et al. (2015) Relation of baseline plasma MMP-1 levels to long-term all-cause mortality in patients with known or suspected coronary artery disease referred for coronary angiography. Atherosclerosis 239:268-75|
|Cavusoglu, Erdal; Marmur, Jonathan D; Chhabra, Sandeep et al. (2009) Relation of baseline plasma phospholipid transfer protein (PLTP) activity to left ventricular systolic dysfunction in patients referred for coronary angiography. Atherosclerosis 207:261-5|