Fra‐1 plays a critical role in angiotensin II—induced vascular senescence. Issue 6 (20th March 2019)

• Record Type: Journal Article
• Authors: Yang, Di; Xiao, Chenxi; Long, Fen; Wu, Weijun; Huang, Mengwei; Qu, Lefeng; Liu, Xinhua; Zhu, Yizhun
• Is Part Of: FASEB journal. Volume 33:Issue 6(2019)
• Page Start: 7603
• Page End: 7614
• Publication Date: 2019-03-20
• Subjects: endothelial cells -- p21 -- p16; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201801671RRRR
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Vascular aging has a strong relationship with cardiovascular disease. Fos‐related antigen 1 (Fra‐1), also referred to as Fos‐like antigen 1, is a transcription factor and has been reported to be involved in many pathologic processes. Here, we demonstrate that Fra‐1 plays a critical role in angiotensin II (Ang II)—induced vascular senescence. Fra‐1 expression is increased significantly in Ang II—induced rat aortic endothelial cell (RAEC) senescence and the arteries from Ang II—infused mice. Interestingly, silencing Fra‐1 blocks Ang II—induced senescence phenotypes in RAECs, including decreased senescence‐associated β‐galactosidase staining, and mitigated proliferation suppression and senescence‐associated secretory phenotype. Further, knocking down Fra‐1 inhibits vascular aging phenotypes in an Ang II—infused mice model. The up‐regulated Fra‐1 also exists in human atherosclerotic plaques and Ang II—induced vascular smooth muscle cells as well as in replicated senescence RAECs. Mechanistic studies reveal that Fra‐1 preferentially associates with c‐Jun and binds to the cyclin‐dependent kinase inhibitor 1a (p21) and cyclin‐dependent kinase inhibitor 2a (p16) promoter region, leading to elevated gene expression, which causes senescence‐related phenotypes. In conclusion, our results identify that Fra‐1 plays a novel and key role in promoting vascular aging by directly binding and transcriptionally activating p21 and p16 signaling, suggesting intervention of Fra‐1 is a potential strategy for preventing aging‐associated cardiovascular disorders.—Yang, D., Xiao, C., Long, F., Wu, W., Huang, M., Qu, L., Liu, X., Zhu, Y. Fra‐1 plays a critical role in angiotensin II—induced vascular senescence. FASEB J. 33, 7603–7614 (2019). www.fasebj.org