Arterial thrombosis resulting from plaque disruption is a leading cause of death due to complications arising from myocardial infarction and stroke. Previous studies demonstrate hypercholesterolemic conditions significantly increase the risk of arterial thrombosis via modification of coagulation proteins. These effects occur through oxidation of lipoproteins and subsequent uptake or activation by inflammatory signaling receptors. Tissue factor (TF), the cellular activator of the clotting cascade, is upregulated via oxidized lipoproteins induced by the inflammatory state in atherosclerotic plaques. This allows for accumulation and concentration of TF in atherosclerotic lesions. Importantly, while TF can create a thrombotic event via plaque rupture and exposure to blood; TF can also activate and signal through a cell associated receptor, protease-activated receptor 2 (PAR2). Our strong preliminary data demonstrates deficiency of PAR2 attenuates early (12 weeks) and advanced (24 weeks) atherosclerosis via non hematopoietic cells. Further, we present extensive preliminary studies demonstrating PAR2 signaling results in vascular smooth muscle cell (VSMC) transdifferentiation into a lipid-laden macrophage-like cell via signaling and activation of krppel-like factor 4 (KLF4) and human antigen R (HuR). Our central hypothesis is that PAR2 regulates VSMC- mediated pathology in atherosclerosis.
In Specific Aim 1 we will determine the molecular mechanism of PAR2-mediated VSMC transdifferentiation via activation of KLF4 and HuR.
In Specific Aim 2, we will determine the role of VSMC-specific PAR2 deletion and pharmacologic PAR2 inhibition in a relevant disease model of atherosclerosis. Together, our studies will increase our understanding of how PAR2 elicits atherosclerosis and may result in a novel therapeutic target to beneficially effect cardiovascular outcomes.
Over the course of decades, lipid accumulation into large blood vessels results in an occlusive disease called atherosclerosis. These atherosclerotic ?plaques? are lipid-rich and develop vulnerable regions that are prone to rupture blocking several key arteries that supply the heart and brain with oxygen rich blood and nutrients resulting in heart attack or stroke, respectively; the number one causes of death worldwide. The goal of this proposal is to explore the molecular mechanisms by which protease-activated receptor 2 (PAR2) mediates cellular changes and inflammation in atherosclerotic disease to enable the scientific and medical community to improve advances in therapeutics and treatment strategies for patients.
