Suppression of FOXC1 induces pyroptosis of the coronary artery through activation of JAK2

• Published in: Atherosclerosis Vol. 396; p. 118543
• Main Authors: Qiu, Jiayun, Fu, Yahong, Tian, Ting, Mao, Yan, Tian, Qiang, Zhou, Lanbo, Jin, Rui, Zhuang, Lili, Zhou, Guoping
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.09.2024
• Subjects: Coronary artery disease; FOXC1; JAK2; Pyroptosis; FOXC1; Pyroptosis; JAK2; Coronary artery disease
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2024.118543

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 ApoeKO 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. [Display omitted] •JAK2 levels increase in patients with CAD and atherosclerotic mice, whereas FOXC1 shows a decreasing trend.•FOXC1 binds to JAK2 and inversely regulates its expression.•FOXC1 regulates pyroptosis and endothelial injury through JAK2 in HCAECs.•FOXC1 is involved in pyroptosis and CAD atherosclerosis by modulating JAK2 in ApoeKO mice.