TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice

Lu, Zhongyang; Zhang, Xiaoming; Li, Yanchun; Jin, Junfei; Huang, Yan

doi:10.1530/joe-12-0338

Cited by 68 publications

(56 citation statements)

References 32 publications

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“…A large body of research has demonstrated that NF-κB and TLR-4 activities are closely associated with lipid metabolism, inflammation and progression of AS [55][56][57][58]. In the absence of TLR-4, the innate immune and inflammatory responses were inhibited and atheromatous plaque sizes were diminished [59][60][61]. NF-κB is a well-known downstream effector of TLR-4, and suppression of LPS-induced NF-κB signaling attenuates atherogenesis [62].…”

Section: Discussionmentioning

confidence: 99%

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Ren

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The development of atherosclerosis is accompanied by escalating inflammation and lipid accumulation within blood vessel walls. ABCA1 plays a crucial role in mediating cholesterol efflux from macrophages, which protects against atherogenesis. This research was designed to explore the effects and underlying mechanisms of apigenin (4’, 5, 7-trihydroxyflavone) on ABCA1-mediated cellular cholesterol efflux and LPS-stimulated inflammation in RAW264.7 macrophages and apoE^-/- mice. Methods: Expression of genes or proteins was examined by RT-PCR or western blot analysis. Liquid scintillation counting was used to detect percent cholesterol efflux. Cellular cholesterol content was measured using HPLC assay. The secretion levels of pro-inflammatory cytokines were quantified by ELISA assay. Atherosclerotic lesion sizes were determined with Oil Red O staining. The contents of macrophages and smooth muscle cells in atherosclerotic lesion were evaluated using immunohistochemistry. Plasma TC, TG, HDL-C and LDL-C levels in apoE^-/- mice were evaluated using commercial test kits. Results: Apigenin potently increased ABCA1 expression through miR-33 repression in a dose- and time-dependent manner. Treatment with apigenin significantly increased ABCA1-mediated cholesterol efflux, and reduced TC, FC and CE levels in macrophage-derived foam cells. In LPS-treated macrophages, the expression levels of TLR-4, MyD88 and p-IκB-α as well as nuclear NF-κB p65 were decreased by the addition of apigenin. Moreover, apigenin markedly decreased secretion levels of several pro-inflammatory cytokines. Lastly, in LPS-challenged apoE^-/- mice, apigenin administration augmented ABCA1 expression, decreased the contents of macrophages and smooth muscle cells in atherosclerotic lesion, reduced miR-33, TLR-4, and NF-κB p65 levels, improved plasma lipid profile and relieved inflammation, which results in less atherosclerotic lesion size. Conclusions: Taken together, these results suggest that apigenin may attenuate atherogenesis through up-regulating ABCA1-mediated cholesterol efflux and inhibiting inflammation.

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Section: Discussionmentioning

confidence: 99%

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Ren

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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“…It also inhibits vascular inflammation and atherogenesis in diabetic apolipoprotein E-deficient mice (Lu et al 2013). …”

Section: Introductionmentioning

confidence: 99%

LPS-RS attenuation of lipopolysaccharide-induced acute lung injury involves NF-κB inhibition

Abdelmageed

El‐Awady

Abdelrahim

et al. 2016

Can. J. Physiol. Pharmacol.

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In this study, we studied the effect of lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), an inhibitor of Toll-like receptor 4 (TLR4), in LPS-induced acute lung injury (ALI). Male Sprague-Dawley rats were treated with LPS-RS (0.1 mg/kg body mass, by intraperitoneal (i.p.) injection) 1 h before LPS injection (10 mg/kg, i.p.). Bronchoalveolar lavage fluid (BALF) and lung tissues were collected 24 h later to determine total and differential cell count, total protein content, levels of lactate dehydrogenase (LDH), histopathological changes, markers of oxidative stress, and mRNA expression of the inhibitory protein nuclear factor kappaB-α (NFκBIA) and TLR4. Additionally, rings of pulmonary artery were isolated for measuring vascular reactivity. LPS-induced ALI was indicated by increases in total and differential cell count, total protein, and LDH in BALF, and increased lung levels of malondialdehyde (MDA), as well as decreased activity of reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, LPS increased pulmonary artery contraction in response to phenylephrine (PE). Additionally, LPS downregulated mRNA expression of NFκBIA and upregulated mRNA expression of TLR4. LPS caused a marked inflammation in the lung tissue, with tubercular granuloma and numerous neutrophils. Pretreatment with LPS-RS protected against LPS-induced ALI by decreasing total and differential cell count, total protein, and LDH in BALF, and increased pulmonary GSH content and SOD activity without affecting MDA content. Additionally, it decreased the elevated PE-induced pulmonary artery contraction. LPS-RS upregulated mRNA expression of NFκBIA and downregulated mRNA expression of TLR4. Moreover, LPS-RS prevented inflammation in lung tissues. In conclusion, pretreatment with LPS-RS protects against LPS-induced ALI in rats through its anti-inflammatory effects, possibly by decreasing the mRNA expression of TLR4 and increasing that of NFκBIA.

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“…In contrast, the link between P.g LPS-and AGEs-mediated dysregulation of cholesterol metabolism has not fully been cleared. Blocking NF-kB activation has been regarded as an efficient approach to attenuate atherosclerotic plaque formation [9,20,21], suggesting that upstream modulators in NF-kB activation might be helpful to elucidate the underlying mechanism among PRRs-mediated signaling pathways associated with the dysregulation of cholesterol metabolism. miR-146a, one member of the miRNA-146 family, is an important modulator of differentiation and function of cells in innate and adaptive immunity.…”

mentioning

confidence: 99%

miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation

et al. 2015

Inflammation

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The miR-146-mediated IL-1 receptor-associated kinase 1 (IRAK-1) feedback circuit has been shown to inhibit inflammatory response in macrophages against lipopolysaccharide (LPS). The aim of this study is to compare the antagonized effects of miR-146a-5p on Porphyromonas gingivalis (P.g) lipolysaccharide (LPS)- and advanced glycation end products (AGEs)-triggered ABCA1 and ABCG1 dysregulation and explore the underlying mechanism. THP-1-derived macrophages transfected with miRNA mimics or not were treated with P.g LPS or AGE-BSA, respectively. The mechanism of endotoxin tolerance was mimicked. miR-146a-5p levels and protein levels of IRAK-1, LXRα/β, ABCA1, and ABCG1 were detected by stem-loop reverse transcription followed by TaqMan PCR analysis and Western blotting. Our results showed that miR-146a-5p levels were significantly increased in macrophages after 24 h of stimulation with high dose of P.g LPS or AGE-BSA. Macrophages transfected with miR-146a-5p mimics attenuated the dysregulation of ABCA1/G1 induced by P.g LPS and AGEs through IRAK-1 downregulation. In low-dose LPS-tolerized cells, elevated miR-146a-5p antagonized the increase of ABCA1, ABCG1, and IRAK-1. However, low-dose AGE-BSA did not increase miR-146a-5p levels. In conclusion, the model of endotoxin tolerance is suitable for the antagonistic effects on the dysregulation of ABCA1/G1 induced by high dose of P.g LPS. Conversely, low-dose AGEs did not induce the model of P.g LPS-mediated tolerance.

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TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice

Cited by 68 publications

References 32 publications

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

LPS-RS attenuation of lipopolysaccharide-induced acute lung injury involves NF-κB inhibition

miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation

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