Andrographolide Ameliorates Aortic Lesion via Inhibition of NF-κB Signaling Pathway in Angiotensin-II Treated Murine Model of Abdominal Aortic Aneurysm

However, the role of Andrographolide in the development and progression of AAA remains elusive.

Methods

Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline-treated mice and those treated with Ang II for 14 or 28 days. Vascular smooth muscle cells (VSMCs) differentiation markers and plasma Elisa were used to evaluate vascular phenotypic switching and inflammation. We used Andrographolide (an NFκB1 inhibitor) for the pre-treatment of vascular lesions before AAA formation and explored the underlying mechanisms through transcriptomic and functional studies.

Results: We demonstrated that the NFκB signaling pathway contributes to the phenotypic switch and inflammation of vascular smooth muscle cells (VSMCs), with NFκB1 identified as a potential key gene for AAA development, particularly in the early stages of the aneurysm. Andrographolide significantly attenuated vascular lesions at the early stage and reduced aneurysm formation at the later stages of the disease in Ang II-treated AAA mice.

Our ChIP results further demonstrated that NFκB1 regulates its direct target KLF4 to induce VSMC dedifferentiation. Meanwhile, TNF-alpha was identified as a target of NFκB1, indicating that NFκB1 exacerbates inflammation via the TNF-alpha signaling pathway. Discussion: Our results demonstrate a previously unrecognized role of vascular lesions in AAA development and progression, and the pre-treatment with Andrographolide may serve as a novel therapeutic approach for AAA.