From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.).
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (H.A.C.-F., G.E.C.-A., C.R., S.H.-R., D.J.H., S.G.).
Arterioscler Thromb Vasc Biol. 2019 Mar;39(3):387-401. doi: 10.1161/ATVBAHA.118.311903.
Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.
动脉粥样硬化性冠状动脉疾病是全球范围内导致死亡的主要原因，而目前的治疗选择还不够充分。我们之前使用大规模冠状动脉疾病病例对照队列进行系统水平的网络聚类分析，发现 PCSK3（脯氨酸羧肽酶/丝氨酸羧肽酶家族成员 3；furin）是几种与冠状动脉疾病相关途径的成员。因此，我们的目标是确定 furin 在动脉粥样硬化中的作用。
在体外，furin 抑制剂治疗导致单核细胞迁移减少，巨噬细胞和血管内皮细胞炎症和细胞因子基因表达减少。在体内，给予高脂血症 Ldlr 小鼠不可逆的 furin 抑制剂α-1-PDX（α1-抗胰蛋白酶波特兰），可降低动脉粥样硬化病变面积，并特异性减少严重病变。观察到病变巨噬细胞和胶原面积以及系统性炎症标志物明显降低。MMP2（基质金属蛋白酶 2）是内皮功能和动脉粥样硬化病变进展的效应物，也是 furin 的底物，在抑制剂治疗小鼠的主动脉中显著减少。为了确定 furin 在血管内皮功能中的作用，我们给携带普通颈动脉wire 损伤的 Apoe 小鼠给予α-1-PDX。我们观察到颈动脉内膜厚度明显降低，斑块细胞密度降低，平滑肌细胞、巨噬细胞和炎症标志物含量降低，提示对血管重塑的保护作用。在该模型中过表达 furin 导致内膜斑块厚度显著增加 67%，证实 furin 水平与动脉粥样硬化直接相关。
我们表明，在小鼠中全身性抑制 furin 可减少血管重塑和动脉粥样硬化。furin 介导的 MMP2 活性调节可能有助于解释这些小鼠中观察到的动脉粥样保护作用。
