Abstract
Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by aortic dilatation and predominantly affects an elderly population. Accumulating evidence suggests that Interleukin-6 (IL-6) and the signal transducer and activator of transcription 3 (STAT3) play an important role in formation of AAAs. However, it remains unclear whether Bazedoxifene (BAZ) could suppress the activation of IL-6/GP130/STAT3 in vascular cells and the formation of AAA. Here we explored the effect of BAZ on AngII-stimulated AAA formation. ApoE–/– mice infused with AngII for 28 days using osmotic minipumps were treated with placebo or 5mg/kg BAZ. In our results most of the AngII-induced mice developed AAA with exacerbated inflammation, degradation of elastin fibers, STAT3 phosphorylation, and increased expression of matrix metalloproteinases (MMPs). These effects were markedly attenuated by BAZ. Furthermore, BAZ suppressed the stimuli-induced (IL-6 or AngII) expression of P-STAT3, MMP2 and MMP9 in vascular smooth muscle cells (VSMCs). BAZ inhibited wound healing, colony formation and suppressed STAT3 nuclear translocation in vitro. In conclusion, these results indicated that BAZ downregulated IL-6/GP130/STAT3 signaling and interfered with AAA formation induced by AngII in ApoE–/– mice, which indicates a novel potential strategy for the prevention and therapy of AAA.
Highlights
Abdominal aortic aneurysm (AAA) is a potentially lifethreatening degenerative vascular disease affecting 6% to 9% of men over the age of 65 years, with an annual death toll of more than 15,000 (Baxter et al, 2008; Wang et al, 2013; Argyriou et al, 2018)
We found that BAZ attenuated the development and severity of AngII-stimulated AAA in ApoE−/− mice and that BAZ could suppress the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of MMP2 and MMP9
We detected the suppressive effect of BAZ in the development of abdominal aortic aneurysm in AngII-induced mice
Summary
Abdominal aortic aneurysm (AAA) is a potentially lifethreatening degenerative vascular disease affecting 6% to 9% of men over the age of 65 years, with an annual death toll of more than 15,000 (Baxter et al, 2008; Wang et al, 2013; Argyriou et al, 2018). There is an existing gap in the study of the occurrence and development of AAA, suggesting that exploring potential mechanisms could play a critical role in the prevention and treatment of abdominal aortic aneurysm in clinical work. MMPs, MMP2 and MMP9, degrade the extracellular matrix and elastic fibers leading to the development and progression of AAA (Dilme et al, 2014; Ghosh et al, 2015)
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