ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm

Area of Science:

• Vascular Biology
• Immunology
• Molecular Mechanisms

Background:

• Macrophage activation is crucial in abdominal aortic aneurysm (AAA) development.
• Molecular pathways governing macrophage activation and vascular inflammation in AAA are not fully understood.

Purpose of the Study:

• To investigate the role of adenosine deaminase acting on RNA 1 (ADAR1) in macrophage activation and AAA formation.
• To elucidate novel mechanisms of ADAR1 function in the context of AAA.

Main Methods:

• Utilized aortic transplantation and an Ang II-infused ApoE-/- mouse model with macrophage-specific ADAR1 knockout.
• Examined ADAR1's relevance in human AAA specimens and established a humanized AAA model.
• Assessed effects on macrophage infiltration, inflammation, and NF-κB signaling.

Main Results:

• Nonvascular ADAR1 and macrophage ADAR1 are essential for AAA development.
• ADAR1 deficiency reduced AAA prevalence/severity, inhibited macrophage infiltration, and diminished NF-κB signaling.
• ADAR1 promotes Drosha degradation, inhibiting microRNA processing targeting IKKβ, thereby enhancing NF-κB signaling and inflammation.
• ADAR1 and Drosha interaction was observed in human AAA lesions, and human ADAR1-deficient monocytes blocked aneurysm formation in a humanized model.

Conclusions:

• Macrophage ADAR1 drives aneurysm formation in both mouse and human arteries via Drosha degradation.
• This novel mechanism suppresses anti-inflammatory microRNAs targeting NF-kB signaling, promoting vascular inflammation in AAA.