Contribution of TLR4 signaling in intermittent hypoxia-mediated atherosclerosis progression.

ABSTRACT: BACKGROUND:Intermittent hypoxia (IH), a typical character of obstructive sleep apnea (OSA), is related to atherogenesis. However, the role of IH on atherosclerosis (AS) progression and the mechanisms involved remains poorly understood. METHODS:In the present study, high-fat fed ApoE-/- mice were treated with recombinant shRNA-TLR4 lentivirus and exposed to IH. Atherosclerotic lesions on the en face aorta and cross-sections of aortic root were examined by Oil-Red O staining. The content of lipids and collagen of aortic root plaques were detected by Oil-Red O staining and Sirius red staining, respectively. The TLR4, NF-?B p65, ?-SMA and MOMA-2 expression in aorta and IL-6 and TNF-? expression in the mice serum were also detected. RESULTS:Compared with the Sham group, the IH treated group further increased atherosclerotic plaque loads and plaque vulnerability in the aortic sinus. Along with increased TLR4 expression, enhanced NF-?B activation, inflammatory activity and aggravated dyslipidemia were observed in the IH treated group. TLR4 interference partly inhibited IH-mediated AS progression with decreased inflammation and improved cholesterol levels. Similarly, in endothelial cells, hypoxia/reoxygenation exposure has been shown to promote TLR4 expression and activation of proinflammatory TLR4/NF-?B signaling, while TLR4 interference inhibited these effects. CONCLUSIONS:We found that the IH accelerated growth and vulnerability of atherosclerotic plaque, which probably acted by triggering the activation of proinflammatory TLR4/NF-?B signaling. These findings may suggest that IH is a risk factor for vulnerable plaque and provide a new insight into the treatment of OSA-induced AS progression.

SUBMITTER: Zeng X 

PROVIDER: S-EPMC5907703 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature