Contribution of TLR4 signaling in intermittent hypoxia-mediated atherosclerosis progression

Abstract

BackgroundIntermittent 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.MethodsIn 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-κB p65, α-SMA and MOMA-2 expression in aorta and IL-6 and TNF-α expression in the mice serum were also detected.ResultsCompared 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-κB 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-κB signaling, while TLR4 interference inhibited these effects.ConclusionsWe found that the IH accelerated growth and vulnerability of atherosclerotic plaque, which probably acted by triggering the activation of proinflammatory TLR4/NF-κB 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.

Research Progress on the Relationship between Atherosclerosis and Inflammation

“…In human aortic SMC, LPS stimulates TLR4 signaling to promote the release of MCP-1, IL-1α, and IL-6 [ 53 ]. Contribution of TLR4 signaling in intermittent hypoxia-mediated atherosclerosis progression [ 54 ]. So TLR4 signaling maybe an ideal target for interfering in the AS progression.…”

“…However, inhibition of NF-κB activation in macrophages causes a reduction of foam cell formation, anti-apoptosis, and anti-inflammation [ 58 ]. Triggering the activation of TLR4/NF-κB signaling and the downstream proinflammatory responses promotes the plaque growth and instability [ 54 ].…”

Aquaporin 7 involved in GINSENOSIDE-RB1-mediated anti-obesity via peroxisome proliferator-activated receptor gamma pathway

“…Serum collected from each mouse was centrifuged at 3000 rpm for 15 min and stored at − 80°C for further analysis. Blood biochemical tests to detect serum lipids (cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and free fatty acid) and blood glucose were performed as described in our previous report [18].…”

Oscillatory Shear Stress Induces Oxidative Stress via TLR4 Activation in Endothelial Cells

“…TLRs, membrane-spanning proteins, have been implicated in the progression and development of many chronic diseases [15]. TLR4 has also been implicated in the development and progression of cardiovascular disease by inducing endothelial dysfunction [8, 10]. Study showed that TLR4 knockout led to marked reduction of aortic plaque area, decreased inflammation, and reduced oxidative damage [16].…”

“…Recently, a growing body of evidence has elucidated their role in regulating the inflammatory response and maintaining endothelial homeostasis [5]. TLR4, the first identified TLR, has also been implicated in the development and progression of cardiovascular disease [8, 9]. Several studies have reported a role of TLR4 in promoting ECs proliferation and neointima formation [10].…”