Cirillo Plinio, Conte Stefano, Pellegrino Grazia, Ziviello Francesca, Barra Giusi, De Palma Raffaele, Leonardi Antonio, Trimarco Bruno
Division of Cardiology, Department of Advanced Biological Sciences, University of Naples "Federico II", Via Sergio Pansini 5, 80131, Naples, Italy.
Division of Cardiology, Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples, Italy.
J Thromb Thrombolysis. 2016 Aug;42(2):225-32. doi: 10.1007/s11239-016-1353-4.
Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase with a controversial role in pathophysiology of cardiovascular disease. It seems involved in progression of atherosclerosis and is widely represented in atherosclerotic plaque. PAPP-A plasma levels are elevated in patients with acute coronary syndromes (ACS), thus it has been suggested that it might be a prognostic marker for developing major cardiovascular events. However, the pathophysiological link(s) between PAPP-A and ACS are still unknown. Several studies have indicated that tissue factor (TF) plays a pivotal role in the pathophysiology of ACS by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates whether PAPP-A, at concentrations measurable in ACS patients, might induce TF expression in human endothelial cells in culture (HUVEC). In HUVEC, PAPP-A induced TF-mRNA transcription as demonstrated by real time PCR and expression of functionally active TF as demonstrated by FACS analysis and pro-coagulant activity assay. PAPP-A induced TF expression through the activation of Akt/NF-κB axis, as demonstrated by luciferase assay and by suppression of TF-mRNA transcription as well as of TF expression/activity by Akt and NF-κB inhibitors. These data indicate that PAPP-A promotes TF expression in human endothelial cells and support the hypothesis that this proteinase, besides being involved in progression of atherosclerosis, does not represent an independent risk factor for adverse cardiovascular events, but it rather might play an "active" role in the pathophysiology of ACS as an effector molecule able to induce a pro-thrombotic phenotype in endothelial cells.
妊娠相关血浆蛋白-A（PAPP-A）是一种金属蛋白酶，在心血管疾病的病理生理学中具有争议性作用。它似乎参与动脉粥样硬化的进展，并且在动脉粥样硬化斑块中广泛存在。急性冠状动脉综合征（ACS）患者的血浆PAPP-A水平升高，因此有人提出它可能是发生重大心血管事件的预后标志物。然而，PAPP-A与ACS之间的病理生理联系仍不清楚。多项研究表明，组织因子（TF）通过在内皮损伤后触发冠状动脉内血栓形成，在ACS的病理生理学中起关键作用。本研究调查了在ACS患者中可测量浓度的PAPP-A是否可能诱导培养的人内皮细胞（HUVEC）中TF的表达。在HUVEC中，实时PCR显示PAPP-A诱导TF-mRNA转录，流式细胞术分析和促凝血活性测定显示其诱导功能活性TF的表达。荧光素酶测定以及Akt和NF-κB抑制剂抑制TF-mRNA转录以及TF表达/活性表明，PAPP-A通过激活Akt/NF-κB轴诱导TF表达。这些数据表明，PAPP-A促进人内皮细胞中TF的表达，并支持以下假设：这种蛋白酶除了参与动脉粥样硬化的进展外，不是不良心血管事件的独立危险因素，而是可能在ACS的病理生理学中作为一种能够在内皮细胞中诱导促血栓形成表型的效应分子发挥“积极”作用。
