The role of protease-activated receptor 2 in atherosclerosis

摘要 斑块破裂导致的动脉血栓形成是由于并发症导致死亡的主要原因 由心肌梗塞和中风引起。先前的研究表明高胆固醇血症 这些病症通过凝血蛋白的修饰显著增加动脉血栓形成的风险。 这些作用通过脂蛋白的氧化和随后的摄取或激活发生， 炎症信号受体。组织因子（TF）是凝血级联反应的细胞激活剂， 通过动脉粥样硬化斑块中炎症状态诱导的氧化脂蛋白上调。 这使得TF在动脉粥样硬化病变中蓄积和浓缩。重要的是，虽然TF 可通过斑块破裂和暴露于血液引起血栓形成事件; TF也可激活和 通过细胞相关受体蛋白酶激活受体2（PAR 2）进行信号传导。我们强大 初步数据表明PAR 2的缺乏在早期（12周）和晚期（24周）减弱 周）动脉粥样硬化。此外，我们提出了广泛的初步 研究表明PAR 2信号转导导致血管平滑肌细胞（VSMC） 通过krüppel样信号传导和激活转分化为脂质负载的巨噬细胞样细胞 因子4（KLF 4）和人抗原R（HuR）。我们的中心假设是PAR 2调节VSMC- 介导的动脉粥样硬化病理。在具体目标1中，我们将确定分子机制 PAR 2通过激活KLF 4和HuR介导的VSMC转分化。在具体目标2中， 将确定VSMC特异性PAR 2缺失和药理学PAR 2抑制在 动脉粥样硬化相关疾病模型。总之，我们的研究将增加我们对 PAR 2如何诱发动脉粥样硬化，并可能导致新的治疗靶点， 心血管结局。

ABSTRACT 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 krüppel-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.