Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, China.
Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, China.
Atherosclerosis. 2024 Sep;396:118543. doi: 10.1016/j.atherosclerosis.2024.118543. Epub 2024 Jul 17.
Janus kinase 2 (JAK2) triggers endothelial pyroptosis and is associated with a multitude of pathological cardiovascular manifestations, including atherosclerosis. However, the associated transcriptional regulatory mechanisms remain unclear. In this study, we investigated a novel transcriptional regulator upstream of JAK2.
We validated the binding and regulation of Forkhead box C1 (FOXC1) and JAK2 using chromatin immunoprecipitation and luciferase reporter assays. Immunofluorescence was used to detect protein localization in cells and tissues. Immunohistochemistry, hematoxylin-eosin (HE), Masson's trichrome, and Oil Red O staining were used to identify tissue lesions. Transcriptional functions were investigated using in vitro and in vivo coronary artery disease (CAD) atherosclerosis models.
The mRNA levels of JAK2 were considerably higher in both the cardiac tissues of mice and the peripheral blood of patients with CAD than in equivalent controls. JAK2 expression increased markedly in the coronary arteries of Apoe mice, whereas FOXC1 expression exhibited a decreasing trend. In vitro, FOXC1 bound to the JAK2 promoter region and inversely regulated the expression of JAK2. Mechanistic studies have revealed that the FOXC1-JAK2 pathway regulates pyroptosis and participates in the pathogenesis of human coronary artery endothelial cells (HCAECs). In vivo, the suppression of FOXC1 was confirmed to stimulate the levels of JAK2 and pyroptosis, contributing to the pathological progression of aortic and coronary artery damage.
We established the FOXC1-JAK2 regulatory pathway and verified its reverse-regulatory function in CAD pyroptosis. Our data emphasizes that FOXC1 is critical for the treatment of pyroptosis-induced injury in patients with CAD.
Janus 激酶 2（JAK2）触发内皮细胞焦亡，并与多种病理心血管表现相关，包括动脉粥样硬化。然而，相关的转录调控机制尚不清楚。在本研究中，我们研究了 JAK2 的一个新的上游转录调控因子。
我们使用染色质免疫沉淀和荧光素酶报告基因检测验证了 Forkhead box C1（FOXC1）和 JAK2 的结合和调控。免疫荧光用于检测细胞和组织中的蛋白质定位。免疫组织化学、苏木精-伊红（HE）、马松三色和油红 O 染色用于鉴定组织病变。使用体外和体内冠状动脉疾病（CAD）动脉粥样硬化模型研究转录功能。
与对照相比，CAD 患者的心脏组织和外周血中的 JAK2 mRNA 水平明显更高。在 Apoe 小鼠的冠状动脉中，JAK2 表达显著增加，而 FOXC1 表达呈下降趋势。体外，FOXC1 与 JAK2 启动子区域结合，并反向调节 JAK2 的表达。机制研究表明，FOXC1-JAK2 途径调节焦亡并参与人冠状动脉内皮细胞（HCAEC）的发病机制。在体内，FOXC1 的抑制被证实会刺激 JAK2 和焦亡的水平，导致主动脉和冠状动脉损伤的病理进展。
我们建立了 FOXC1-JAK2 调控途径，并验证了其在 CAD 焦亡中的反向调节功能。我们的数据强调，FOXC1 对于治疗 CAD 患者的焦亡诱导损伤至关重要。
