Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.
Eur Heart J. 2023 May 21;44(20):1818-1833. doi: 10.1093/eurheartj/ehac641.
Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis.
JCAD knockout (Jcad-/-) mice underwent photochemically induced endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with JCAD small interfering RNA (siJCAD), LATS2 small interfering RNA (siLATS2) or control siRNA (siSCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome or ST-elevation myocardial infarction (STEMI). Jcad-/- mice displayed reduced thrombogenicity as reflected by delayed time to carotid occlusion. Mechanisms include reduced activation of the coagulation cascade [reduced tissue factor (TF) expression and activity] and increased fibrinolysis [higher thrombus embolization episodes and D-dimer levels, reduced vascular plasminogen activator inhibitor (PAI)-1 expression]. In vitro, JCAD silencing inhibited TF and PAI-1 expression in HAECs. JCAD-silenced HAECs (siJCAD) displayed increased levels of LATS2 kinase. Yet, double JCAD and LATS2 silencing did not restore the control phenotype. si-JCAD HAECs showed increased levels of phosphoinositide 3-kinases (PI3K)/ proteinkinase B (Akt) activation, known to downregulate procoagulant expression. The PI3K/Akt pathway inhibitor-wortmannin-prevented the effect of JCAD silencing on TF and PAI-1, indicating a causative role. Also, co-immunoprecipitation unveiled a direct interaction between JCAD and Akt. Confirming in vitro findings, PI3K/Akt and P-yes-associated protein levels were higher in Jcad-/- animals. Lastly, as compared with chronic coronary syndrome, STEMI patients showed higher plasma JCAD, which notably correlated positively with both TF and PAI-1 levels.
JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis.
连接黏附蛋白 5 相关变异体（JCAD）与急性冠状动脉综合征相关联。JCAD 通过大肿瘤抑制激酶 2（LATS2）/Hippo 通路促进实验性动脉粥样硬化。本研究旨在研究 JCAD 在动脉血栓形成中的作用。
通过光化学诱导内皮损伤，使 JCAD 敲除（Jcad-/-）小鼠发生动脉血栓形成。用 JCAD 小干扰 RNA（siJCAD）、LATS2 小干扰 RNA（siLATS2）或对照 siRNA（siSCR）处理原代人主动脉内皮细胞（HAECs），进行体外实验。检测慢性冠状动脉综合征或 ST 段抬高型心肌梗死（STEMI）患者的血浆 JCAD。Jcad-/- 小鼠的血栓形成能力降低，表现为颈动脉闭塞时间延迟。其机制包括凝血级联反应的活性降低[组织因子（TF）表达和活性降低]和纤维蛋白溶解增加[血栓栓塞事件和 D-二聚体水平增加，血管纤溶酶原激活物抑制剂（PAI-1）表达降低]。在体外，JCAD 沉默抑制了 HAECs 中的 TF 和 PAI-1 表达。JCAD 沉默的 HAECs（siJCAD）中 LATS2 激酶水平升高。然而，双重 JCAD 和 LATS2 沉默并不能恢复对照表型。si-JCADHAECs 中磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）的激活水平升高，已知其可下调促凝表达。PI3K/Akt 通路抑制剂wortmannin 可阻止 JCAD 沉默对 TF 和 PAI-1 的作用，表明其具有因果关系。此外，共免疫沉淀揭示了 JCAD 和 Akt 之间的直接相互作用。与体外研究结果一致，Jcad-/- 动物的 PI3K/Akt 和 P-yes 相关蛋白水平更高。最后，与慢性冠状动脉综合征相比，STEMI 患者的血浆 JCAD 水平更高，其水平与 TF 和 PAI-1 水平呈正相关。
JCAD 通过调节凝血和纤维蛋白溶解促进动脉血栓形成。本研究的转化数据表明，JCAD 可能是动脉血栓形成的潜在治疗靶点。
