Abstract
The interaction between atherosclerosis and commensal microbes through leaky gut syndrome (LGS), which is characterized by impaired intestinal permeability and the introduction of undesired pathogens into the body, has not been fully elucidated. Our aim was to investigate the potential role of a ClC-2 chloride channel activator, lubiprostone, which is reported to have beneficial effects on LGS, in the development of atherosclerosis in apolipoprotein E–deficient (ApoE-/-) mice. After a 15-week feeding period of a Western diet (WD), ApoE-/- mice were treated with a Western-type diet (WD) alone or WD with oral supplementation of lubiprostone for 10 weeks. This feeding protocol was followed by experimental evaluation of LGS and atherosclerotic lesions in the aorta. In mice with lubiprostone, in vivo translocation of orally administered 4-kDa FITC-dextran was significantly improved, and RNA expression of the epithelial tight junction proteins, Zo-1 and occludin, was significantly up-regulated in the ileum, compared to the WD alone group, suggesting a possible reversal of WD-induced intestinal barrier dysfunction. As a result, WD-induced exacerbation of atherosclerotic lesion formation was reduced by 69% in longitudinally opened aortas and 26% in aortic root regions. In addition, there was a significant decrease in circulating immunoglobulin level, followed by an attenuation of inflammatory responses in the perivascular adipose tissue, as evidenced by reduced expression of pro-inflammatory cytokines and chemokines. Lubiprostone attenuates atherosclerosis by ameliorating LGS-induced inflammation through the restoration of the intestinal barrier. These findings raise the possibility of targeting LGS for the treatment of atherosclerosis.
Highlights
Atherosclerosis is the leading cause of cardiovascular mortality and morbidity worldwide
These results indicate that oral supplementation with lubiprostone attenuated Western diet (WD)-induced exacerbation of atherosclerotic lesion formation but was not sufficient to induce regression of atherosclerotic plaques
The genes encoding inflammation-activation related molecules, including interleukin 1 beta (IL1β) and tumor necrosis factor receptor alfa (TNFα), were significantly down-regulated only in lubiprostone-supplemented mice (Fig 5D and 5E). These findings strongly indicate that the observed effects of lubiprostone supplementation in attenuating the inflammatory phenotype of perivascular adipose tissue (PVAT) and suppressing the development of atherosclerosis were mediated via inactivation of the B2-cell toll-like receptor (TLR) signaling pathway
Summary
Atherosclerosis is the leading cause of cardiovascular mortality and morbidity worldwide. Recent studies have revealed that atherosclerosis arises from a systemic inflammatory process, including the accumulation and the activities of immune cells [1, 2]. Ministry of Education, Culture, Sports, Science, and Technology (MEXT) no. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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