Taxifolin ameliorates abdominal aortic aneurysm by preventing inflammation and apoptosis and extracellular matrix degradation via inactivating TLR4/NF-κB axis

Background: Abdominal aortic aneurysm (AAA) is a serious aortic disease with high mortality. Vascular smooth muscle cells (VSMCs) loss is a prominent feature of AAA. Taxifolin (TXL) is a natural antioxidant polyphenol and possesses therapeutic functions in numerous human diseases. This study aimed to investigate TXL's impact on VSMC phenotype in AAA.

Methods: In vitro and in vivo of VSMC injury model was induced by angiotensin II (Ang II). The potential function of TXL on AAA was determined using Cell Counting Kit-8, flow cytometry, Western blot, quantitative reverse transcription-PCR, and enzyme-linked immunosorbent assay. Meanwhile, TXL mechanism on AAA was checked by a series of molecular experiments. Also, TXL function on AAA in vivo was further evaluated using hematoxylin-eosin staining, TUNEL assay, Picric acid-Sirius red staining and immunofluorescence assay in C57BL/6 mice.

Results: TXL alleviated Ang II-induced VSMC injury mainly by enhancing VSMC proliferation and weakening cell Apoptosis, alleviating VSMC inflammation, and reducing extracellular matrix (ECM) degradation of VSMCs. Furthermore, mechanistic studies corroborated that TXL reversed the high levels of Toll-like Receptor 4 (TLR4) and p-p65/p65 induced by Ang II. Also, TXL facilitated VSMC proliferation and reduced cell Apoptosis, repressed inflammation, and ECM degradation of VSMCs, while these effects were reversed by TLR4 overexpression. In vivo studies further confirmed that TXL owned the function of alleviating AAA, such as alleviating collagen fiber hyperplasia and inflammatory cell infiltration in AAA mice, and repressing inflammation and ECM degradation.

Conclusion: TXL protected VSMCs against Ang II-induced injury through activating TLR4/noncanonical nuclear factor-kappaB(NF-κB).

Abdominal aortic aneurysm; NF-κB; TLR4; Taxifolin; Vascular smooth muscle cells.