ATF4 Contributes to Abdominal Aortic Aneurysm Formation via Modulating M1 Macrophage Polarization and Inflammation

Area of Science:

• Vascular Biology
• Immunology
• Molecular Medicine

Background:

• Abdominal aortic aneurysm (AAA) is a serious vascular condition lacking effective medical treatments.
• Activating Transcription Factor 4 (ATF4) is implicated in cardiovascular diseases, but its role in AAA pathogenesis is unknown.

Purpose of the Study:

• To investigate the role of Activating Transcription Factor 4 (ATF4) in the development of abdominal aortic aneurysm (AAA).
• To explore ATF4's mechanism in AAA, focusing on its interaction with macrophages and inflammatory responses.

Main Methods:

• Analysis of ATF4 expression in human AAA patients and mouse models.
• Utilizing mouse models with ATF4 knockdown and macrophage-specific knockout.
• Employing RNA sequencing, ChIP sequencing, and ChIP analyses to identify ATF4 target genes.

Main Results:

• ATF4 expression was significantly elevated in AAA patients and models, primarily in arterial macrophages.
• ATF4 deficiency attenuated AAA formation, while overexpression promoted it.
• ATF4 regulates macrophage M1 polarization via Sphingomyelin phosphodiesterase 3 (SMPD3), enhancing inflammation and promoting AAA.

Conclusions:

• ATF4 promotes AAA development by inducing macrophage M1 polarization through SMPD3.
• ATF4 represents a potential novel therapeutic target for abdominal aortic aneurysm.