Targeting Nuclear Factor-κB1 With Andrographolide　― Novel Strategy to Inhibit Vascular Lesions and Aneurysm Formation in Abdominal Aortic Aneurysm ―

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease with limited pharmacological treatment to prevent its progression. Whether early prevention of aortic lesions inhibits later formation of AAAs remains unclear. Therefore, this study aimed to investigate whether early intervention could prevent aortic lesion progression and AAA formation, and to explore the underlying molecular mechanisms. METHODS AND RESULTS: Genome-wide RNA sequencing of aortas from saline-treated mice and mice treated with angiotensin (Ang: 1,000 ng/kg/min) II via subcutaneously implanted mini-osmotic pumps for 14 or 28 days showed that nuclear factor (NF)-κB signaling contributes to the phenotypic switch and inflammation, and identified Nfkb1 as a potential key gene in vascular smooth muscle cells (VSMCs) for AAA development. Andrographolide (an NF-κB1 inhibitor) was administered via intraperitoneal injection at a dose of 20 mg/kg/day to pre-treat vascular lesions before AAA formation, and transcriptomic and functional studies were performed to explore the underlying mechanisms. In AngII-treated mice, andrographolide significantly attenuated vascular lesions at the early stage (day 14) and reduced AAA formation at later stages of the disease (day 28). Andrographolide also reduced aortic macrophage infiltration, decreased neutrophil recruitment, and suppressed cytokines. Although detailed mechanistic analyses focused on VSMCs due to their structural predominance in early lesions, chromatin immunoprecipitation (ChIP) further demonstrated that NF-κB1 regulates its direct target Krüppel-like factor 4 to induce VSMC dedifferentiation and tumor necrosis factor (TNF)-α to drive inflammation, indicating that NF-κB1 exacerbates inflammation via TNF-α signaling. CONCLUSIONS: Our results demonstrate a previously unrecognized role of vascular lesions in AAA development and progression. Andrographolide pretreatment may be a novel therapeutic approach for AAA.