Jakobsche-Policht Urszula, Bronowicka-Szydełko Agnieszka, Adamiec Rajmund, Bednarska-Chabowska Dorota, Mierzchała-Pasierb Magdalena, Lewandowski Łukasz, Gostomska-Pampuch Kinga, Adamiec-Mroczek Joanna, Rabczyński Maciej, Kuźnik Edwin, Lubieniecki Paweł, Dróżdż Olgierd, Martynowicz Helena, Kwiecień Anna, Strzelecka Małgorzata, Rudkiewicz Dawid, Piersiak Marcin, Ziomek Maciej, Kondracki Mikołaj, Galińska Zuzanna, Madziarska Katarzyna
Department of Angiology and Internal Diseases, Institute of Internal Diseases, Wroclaw Medical University, Wroclaw, Poland.
Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw, Poland.
Front Mol Biosci. 2025 Sep 9;12:1636893. doi: 10.3389/fmolb.2025.1636893. eCollection 2025.
Protease-activated receptors (PARs), present on the surface of platelets and platelet-derived microparticles (PMPs), belong to a superfamily of membrane receptors that play a key role in initiating intracellular G protein-dependent signaling pathways. Although four types of PARs have been identified-PAR-1, PAR-2, PAR-3, and PAR-4 - their mechanisms and functions remain poorly understood. Nevertheless, they are considered promising therapeutic and diagnostic targets, as they play crucial roles in initiating and promoting processes such as coagulation, inflammatory responses, and vascular function. PAR-1 is expressed on various cell types, including endothelial cells, platelets, neurons, and immune cells. Its activation by thrombin initiates a G protein-dependent signaling cascade that stimulates the expression of cytokines, selectins, adhesion molecules, and growth factors. In addition to thrombin, PAR-1 can also be activated by activated protein C (APC) and matrix metalloproteinase-1 (MMP-1). APC triggers cytoprotective signaling pathways, while MMP-1 influences cellular dynamics through alternative signaling mechanisms. PAR-1 activation is also affected by epigenetic modifications and genetic polymorphisms in the PAR-1 gene. Variants such as -1426 C/T and -506 I/D influence receptor expression and are associated with an increased risk of thrombosis, potentially due to epigenetic changes linked to atherosclerosis. The complex signaling network of PAR-1 makes it a promising therapeutic target for the treatment of cardiovascular diseases, cancer, and neuroinflammatory disorders. This paper serves as a compendium on PAR-1 and its role, particularly in the activation of platelets and PMPs.
蛋白酶激活受体（PARs）存在于血小板和血小板衍生微粒（PMPs）表面，属于膜受体超家族，在启动细胞内G蛋白依赖性信号通路中起关键作用。尽管已鉴定出四种类型的PARs——PAR-1、PAR-2、PAR-3和PAR-4——但其机制和功能仍知之甚少。然而，它们被认为是有前景的治疗和诊断靶点，因为它们在启动和促进凝血、炎症反应和血管功能等过程中发挥着关键作用。PAR-1在包括内皮细胞、血小板、神经元和免疫细胞在内的多种细胞类型上表达。凝血酶对其激活会启动一个G蛋白依赖性信号级联反应，刺激细胞因子、选择素、黏附分子和生长因子的表达。除了凝血酶，PAR-1还可被活化蛋白C（APC）和基质金属蛋白酶-1（MMP-1）激活。APC触发细胞保护信号通路，而MMP-1通过替代信号机制影响细胞动态。PAR-1的激活也受到PAR-1基因表观遗传修饰和基因多态性的影响。-1426 C/T和-506 I/D等变体影响受体表达，并与血栓形成风险增加相关，这可能是由于与动脉粥样硬化相关的表观遗传变化所致。PAR-1复杂的信号网络使其成为治疗心血管疾病、癌症和神经炎症性疾病的有前景的治疗靶点。本文是关于PAR-1及其作用的综述，特别是在血小板和PMPs激活方面的作用。
