Lithium chloride represses abdominal aortic aneurysm via regulating GSK3β/SIRT1/NF-κB signaling pathway

Abstract

Lithium chloride (LiCl), a pharmacological compound, was effective in reducing inflammation, but whether it can protect against abdominal aortic aneurysm (AAA) is largely unknown. This study is designed to investigate therapeutic effects of LiCl on AAA and the potential mechanism. Rat AAA models were induced by periaortic application of CaCl₂. AAA rats were treated by daily intraperitoneal injection of LiCl or vehicle alone to study the protection effects of LiCl in vivo. Rat primary vascular smooth muscle cells (VSMCs) stimulated with tumor necrosis factor (TNF)-α served as an in vitro model. LiCl treatment prevented the development of AAA through inhibiting the inflammatory cells infiltration and inflammatory cytokines overproduction, as well as attenuating superoxide production and elastin degradation in aorta of AAA rats. Additionally, the downregulation of p-GSK3β(Ser9) and SIRT1, upregulation of NF-κB(p-65), MMP-2 and MMP-9 in AAA were abolished by LiCl treatment. In vitro by upregulating p-GSK3β(Ser9), LiCl significantly induced SIRT1 expression, along with inhibition of the NF-κB activation and decreased elastin level elicited in VSMCs by TNF-α stimulation. SIRT1 activator SRT1720 achieved similar repressive effects as LiCl on TNF-α-induced NF-κB activation and decreased elastin in VSMCs. Moreover, administration of LiCl also caused regression of established rats AAA. This study provided the first evidence that LiCl prevented the development of AAA through inhibiting inflammation, MMPs, and superoxide production, and facilitating the biosynthesis of elastin. The beneficial effect of LiCl may be mediated by regulation GSK3β/SIRT1/NF-κB cascade.

Keywords: Abdominal aortic aneurysm; GSK3β; Inflammation; LiCl; Oxidative stress; Vascular smooth muscle cell.