Atherosclerosis remains the underlying cause of the majority of cardiovascular diseases contributing to mortality. Our overall hypothesis is that pathological activation of two blood contact system proteins, factor (F) XI and FXII, mediate platelet-endothelial interactions to promote inflammation and leukocyte trafficking in experimental models of atherosclerotic plaque formation. Our preliminary studies linking contact activation to inflammation and platelet activation suggest that pharmacological targeting of FXI could reduce vascular inflammation, atherogenesis, and its cardiovascular complications, and would be safer than traditional anticoagulants or platelet inhibitors, which carry a significant risk of fatal bleeding. Our work and findings to date have opened the window towards the development of safer antithrombotic strategies. This program will take a new direction to study whether contact activation increases platelet- endothelial cell interactions, leukocyte recruitment and infiltration, and inflammation to promote atherosclerotic plaque formation. This program will build on our ability to develop tools for molecular imaging of cell interactions, the creation of novel inhibitors of contact activation, and rational and responsible use of and translation from in vitro studies to in vivo mouse and non-human primate models of disease.
In Aim 1 we will determine the role of FXI in activating platelets to promote atherogenesis. We will test our hypothesis that FXI-dependent platelet activation promotes recruitment of leukocytes to inflamed endothelium.
In Aim 2 we will determine the role of FXII in promoting inflammation in atherogenesis. We will test our hypothesis that FXII activation of and by FXI induces cytokine and complement generation that contribute to inflammation to promote atherogenesis. We will translate our mechanistic in vitro studies to define the pathological role of contact activation in 2 distinct animal models of atherogenesis. The translational relevance of our project will be the potential identification of safe molecular targets and mechanisms that could support the development of novel pharmacological approaches to address the problem of progressive atherosclerosis.
Our work has pioneered efforts to establish the blood proteins factor XI and XII as novel drug targets to prevent or treat blood clots and reduce inflammation, with limited or no risk of treatment-associated bleeding. Arteriosclerosis narrows arterial blood vessels and can induce blood clots that cause stroke and heart attack and has been associated with chronic blood vessel inflammation, while inherited factor XI deficiency reduces cardiovascular events. We propose that factors XI and XII may be complicit in cardiovascular disease that remains the leading cause of mortality in the country. This project will evaluate whether and how these two proteins contribute to experimental atherosclerosis and inflammation, and determine whether pharmacological inhibition of factors XI or XII could have the potential to slow the progression of atherosclerosis-associated ischemic cardiovascular diseases.
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