From the Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine (T.Z., J.L., X.C., L.Z., H.S., Z.Y., Z.L., Y.Z.), Shanghai East Hospital, Tongji University School of Medicine, China.
Cardiology (J.P., Q.Z.), Shanghai East Hospital, Tongji University School of Medicine, China.
Circ Res. 2019 Aug 30;125(6):590-605. doi: 10.1161/CIRCRESAHA.118.314402. Epub 2019 Jul 18.
Endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, transcriptional regulation of vascular endothelial inflammation has not been well clarified.
This study aims to explore Foxp (forkhead box P) transcription factor 1 in regulation of endothelial homeostasis, atherogenesis, and its mechanisms.
To assess the importance of Foxp1 in atherosclerosis, Foxp1 expression was analyzed in human coronary artery and mouse artery, and we observed significant downregulation of Foxp1 in atherosclerotic and atherosusceptible endothelium. Endothelial-specific Foxp1 knockout mice (Foxp1) were bred onto Apoe mice to generate endothelial Foxp1-deletion hyperlipidemic model Foxp1;Apoe, which displayed significant increases in atherosclerotic lesion formation in aortas and aortic roots with enhanced monocyte adhesion, migration, and infiltration into the vascular wall and formation of inflammatory lipid-laden macrophages. In contrast, endothelial-specific Foxp1 overexpression mice Foxp1;Apoe exhibited reduced atherosclerotic lesion formation with less monocyte infiltration. Foxp1 was further identified as a gatekeeper of vessel inflammation by direct regulation of endothelial inflammasome components, including Nlrp3 (NLR [nucleotide-binding and leucine-rich repeat immune receptors] family pyrin domain containing 3), caspase-1, and IL (interleukin)-1β. Moreover, endothelial Foxp1 was found to be regulated by Klf2 (Kruppel-like factor 2). Oscillatory shear stress downregulated Foxp1 expression via repressing Klf2 expression in endothelium, and, therefore, promoted endothelial inflammasome activation, leading to atherosclerotic lesion formation. Simvastatin upregulated the reduced expression of Klf2 and Foxp1 in atherosusceptible vascular endothelium and alleviated vascular inflammation contributing to its inhibitory effect in atherosclerosis.
These data are the first in vivo experimental validation of an atheroprotective role of endothelial Klf2 and Foxp1, which reveals a Klf2-Foxp1 transcriptional network in endothelial cells as a novel regulator of endothelial inflammasome activation for atherogenesis, therefore, provides opportunities for therapeutic intervention of atherosclerotic diseases and uncovers a novel atheroprotective mechanism for simvastatin.
内皮功能障碍导致持续和慢性血管炎症，这是动脉粥样硬化疾病的核心。然而，血管内皮炎症的转录调控还没有得到很好的阐明。
本研究旨在探讨叉头框蛋白 P1（Foxp1）转录因子在血管内皮稳态、动脉粥样硬化形成及其机制中的作用。
为了评估 Foxp1 在动脉粥样硬化中的重要性，我们分析了人冠状动脉和小鼠动脉中的 Foxp1 表达，发现 Foxp1 在动脉粥样硬化和易患动脉的内皮中显著下调。内皮特异性 Foxp1 敲除小鼠（Foxp1）被繁殖到载脂蛋白 E 基因敲除小鼠（Apoe）上，以产生内皮 Foxp1 缺失的高脂血症模型 Foxp1；Apoe，该模型在主动脉和主动脉根部的动脉粥样硬化病变形成显著增加，单核细胞黏附、迁移和浸润到血管壁以及形成炎症性富含脂质的巨噬细胞增加。相比之下，内皮特异性 Foxp1 过表达小鼠 Foxp1；Apoe 的动脉粥样硬化病变形成减少，单核细胞浸润减少。Foxp1 通过直接调节内皮炎症小体成分，包括 Nlrp3（NLR [核苷酸结合和富含亮氨酸重复免疫受体]家族吡喃结构域包含 3）、半胱天冬酶-1 和白细胞介素-1β，被鉴定为血管炎症的守门员。此外，内皮 Foxp1 受到 Klf2（Kruppel 样因子 2）的调节。振荡剪切力通过抑制内皮细胞中的 Klf2 表达下调 Foxp1 的表达，从而促进内皮炎症小体的激活，导致动脉粥样硬化病变的形成。辛伐他汀上调了易患血管内皮中 Klf2 和 Foxp1 的表达降低，并减轻血管炎症，从而抑制了动脉粥样硬化的形成。
这些数据是内皮 Klf2 和 Foxp1 具有抗动脉粥样硬化作用的首次体内实验验证，揭示了内皮细胞中 Klf2-Foxp1 转录网络作为内皮炎症小体激活导致动脉粥样硬化形成的新型调节剂，为动脉粥样硬化疾病的治疗干预提供了机会，并揭示了辛伐他汀的一种新的抗动脉粥样硬化机制。
