Bonacina F, Barbieri S S, Cutuli L, Amadio P, Doni A, Sironi M, Tartari S, Mantovani A, Bottazzi B, Garlanda C, Tremoli E, Catapano A L, Norata G D
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
IRCCS, Centro Cardiologico Monzino, Milan, Italy.
Biochim Biophys Acta. 2016 Jun;1862(6):1182-90. doi: 10.1016/j.bbadis.2016.03.007. Epub 2016 Mar 11.
The long pentraxin PTX3 plays a non-redundant role during acute myocardial infarction, atherosclerosis and in the orchestration of tissue repair and remodeling during vascular injury, clotting and fibrin deposition. The aim of this work is to investigate the molecular mechanisms underlying the protective role of PTX3 during arterial thrombosis.
PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant reduction in carotid artery blood flow following FeCl3 induced arterial thrombosis (-80.36±11.5% and -95.53±4.46%), while in WT mice transplanted with bone marrow from either WT or PTX3 KO mice, the reduction was less dramatic (-45.55±1.37% and -53.39±9.8%), thus pointing to a protective effect independent of a hematopoietic cell's derived PTX3. By using P-selectin/PTX3 double KO mice, we further excluded a role for P-selectin, a target of PTX3 released by neutrophils, in vascular protection played by PTX3. In agreement with a minor role for hematopoietic cell-derived PTX3, platelet activation (assessed by flow cytometric expression of markers of platelet activation) was similar in PTX3 KO and WT mice as were haemostatic properties. Histological analysis indicated that PTX3 localizes within the thrombus and the vessel wall, and specific experiments with the N-terminal and the C-terminal PTX3 domain showed the ability of PTX3 to selectively dampen either fibrinogen or collagen induced platelet adhesion and aggregation.
PTX3 interacts with fibrinogen and collagen and, by dampening their pro-thrombotic effects, plays a protective role during arterial thrombosis.
长五聚体蛋白3（PTX3）在急性心肌梗死、动脉粥样硬化以及血管损伤、凝血和纤维蛋白沉积过程中的组织修复与重塑协调中发挥着不可或缺的作用。本研究旨在探究PTX3在动脉血栓形成过程中发挥保护作用的分子机制。
移植了野生型（WT）或PTX3基因敲除（KO）小鼠骨髓的PTX3 KO小鼠，在三氯化铁诱导的动脉血栓形成后，颈动脉血流量显著减少（分别为-80.36±11.5%和-95.53±4.46%），而移植了WT或PTX3 KO小鼠骨髓的WT小鼠，血流量减少幅度较小（分别为-45.55±1.37%和-53.39±9.8%），这表明PTX3的保护作用独立于造血细胞衍生的PTX3。通过使用P-选择素/PTX3双基因敲除小鼠，我们进一步排除了PTX3（由中性粒细胞释放的一种靶点）的作用靶点P-选择素在PTX3发挥的血管保护作用中的作用。与造血细胞衍生的PTX3作用较小一致，PTX3 KO小鼠和WT小鼠的血小板活化情况（通过血小板活化标志物的流式细胞术表达评估）以及止血特性相似。组织学分析表明，PTX3定位于血栓和血管壁内，对PTX3 N端和C端结构域进行的特定实验表明，PTX3能够选择性地抑制纤维蛋白原或胶原诱导的血小板黏附和聚集。
PTX3与纤维蛋白原和胶原相互作用，并通过减弱它们的促血栓形成作用，在动脉血栓形成过程中发挥保护作用。
