Cebo Malgorzata, Dittrich Kristina, Fu Xiaoqing, Manke Mailin C, Emschermann Frederic, Rheinlaender Johannes, von Eysmondt Hendrik, Ferreirós Nerea, Sudman Jessica, Witte Alexander, Pelzl Lisann, Borst Oliver, Geisler Tobias, Rath Dominik, Bakchoul Tamam, Gawaz Meinrad, Schäffer Tilman E, Lämmerhofer Michael, Chatterjee Madhumita
Institute of Pharmaceutical Sciences, University of Tübingen, Tübingen, Germany.
Department of Cardiology and Angiology and.
Blood. 2022 Mar 17;139(11):1722-1742. doi: 10.1182/blood.2021013097.
Platelet ACKR3/CXCR7 surface expression is enhanced and influences prognosis in coronary artery disease (CAD) patients, who exhibit a distinct atherothrombotic platelet lipidome. Current investigation validates the potential of ACKR3/CXCR7 in regulating thromboinflammatory response through its impact on the platelet lipidome. CAD patients with enhanced platelet ACKR3/CXCR7 expression exhibited reduced aggregation. Pharmacological CXCR7 agonist (VUF11207) significantly reduced prothrombotic platelet response in blood from acute coronary syndrome patients ex vivo. CXCR7 agonist administration reduced thrombotic functions and thromboinflammatory plateletleukocyte interactions post-myocardial infarction and arterial injury in vivo. ACKR3/CXCR7 ligation did not affect surface availability of surface receptors, coagulation profile, bleeding time, plasma-dependent thrombin generation (thrombinoscopy), or clot formation (thromboelastography) but counteracted activation-induced phosphatidylserine exposure and procoagulant platelet-assisted thrombin generation. Targeted (micro-UHPLC-ESI-QTrap-MS/MS) and untargeted (UHPLCESI-QTOF-MS/MS) lipidomics analysis revealed that ACKR3/CXCR7 ligation favored generation of antithrombotic lipids (dihomo-γ-linolenic acid [DGLA], 12-hydroxyeicosatrienoic acid [12-HETrE]) over cyclooxygenase-1 (COX-1) or 12-lipoxygenase (12-LOX) metabolized prothrombotic and phospholipase-derived atherogenic lipids in healthy subjects and CAD patients, contrary to antiplatelet therapy. Through 12-HETrE, ACKR3/CXCR7 ligation coordinated with Gαs-coupled prostacyclin receptor to trigger cyclic adenosine monophosphate/protein kinase A-mediated platelet inhibition. ACKR3/CXCR7 ligation reduced generation of lipid agonists and lipid signaling intermediates, which affected calcium mobilization, intracellular signaling, and consequently platelet interaction with physiological matrices and thromboinflammatory secretome. This emphasized its functional dichotomy from prothrombotic CXCR4. Moreover, CXCR7 agonist regulated heparin-induced thrombocytopenia-sera/immunoglobulin G-triggered platelet and neutrophil activation, heparin-induced platelet aggregation, generation of thromboinflammatory lipids, platelet-neutrophil aggregate formation, and thromboinflammatory secretion ex vivo. Therefore, ACKR3/CXCR7 may offer a novel therapeutic strategy in acute/chronic thromboinflammation exaggerated cardiovascular pathologies and CAD.
血小板ACKR3/CXCR7的表面表达增强，并影响冠状动脉疾病（CAD）患者的预后，这些患者表现出独特的动脉粥样硬化血栓形成性血小板脂质组。目前的研究证实了ACKR3/CXCR7通过影响血小板脂质组来调节血栓炎症反应的潜力。血小板ACKR3/CXCR7表达增强的CAD患者表现出聚集减少。药理学CXCR7激动剂（VUF11207）在体外显著降低了急性冠状动脉综合征患者血液中的促血栓形成血小板反应。在体内，给予CXCR7激动剂可降低心肌梗死后和动脉损伤后的血栓形成功能以及血栓炎症性血小板与白细胞的相互作用。ACKR3/CXCR7连接不影响表面受体的表面可用性、凝血谱、出血时间、血浆依赖性凝血酶生成（凝血酶镜检查）或凝块形成（血栓弹力图），但可抵消激活诱导的磷脂酰丝氨酸暴露和促凝血小板辅助凝血酶生成。靶向（微量超高效液相色谱-电喷雾电离-四极杆飞行时间串联质谱/MS/MS）和非靶向（超高效液相色谱-电喷雾电离-四极杆飞行时间质谱/MS/MS）脂质组学分析表明，与抗血小板治疗相反，在健康受试者和CAD患者中，ACKR3/CXCR7连接有利于生成抗血栓脂质（二高-γ-亚麻酸[DGLA]、12-羟基二十碳三烯酸[12-HETrE]），而不是环氧化酶-1（COX-1）或12-脂氧合酶（12-LOX）代谢的促血栓形成和磷脂酶衍生的致动脉粥样硬化脂质。通过12-HETrE，ACKR3/CXCR7连接与Gαs偶联的前列环素受体协同作用，触发环磷酸腺苷/蛋白激酶A介导的血小板抑制。ACKR3/CXCR7连接减少了脂质激动剂和脂质信号中间体的生成，这影响了钙动员、细胞内信号传导，进而影响血小板与生理基质和血栓炎症分泌组的相互作用。这强调了它与促血栓形成的CXCR4在功能上的二分法。此外，CXCR7激动剂在体外调节肝素诱导的血小板减少症血清/免疫球蛋白G触发的血小板和中性粒细胞激活、肝素诱导的血小板聚集、血栓炎症脂质的生成、血小板-中性粒细胞聚集体形成以及血栓炎症分泌。因此，ACKR3/CXCR7可能为急性/慢性血栓炎症加剧的心血管疾病和CAD提供一种新的治疗策略。
