Quercetin Attenuates Atherosclerotic Inflammation by Inhibiting Galectin‐3‐NLRP3 Signaling Pathway

Abstract

Scope Atherosclerosis is the underlying pathogenesis of cardiovascular events caused by inflammation, and dietary intervention has been recommended as one fundamental prevention strategy. Herein, the anti‐arteriosclerotic properties of quercetin are investigated by modulating galectin‐3 (Gal‐3)‐NLR family, pyrin domain‐containing 3 (NLRP3) pathway. Methods and results Plaques from ApoE−/− mice fed by high‐fat diet (HFD) with or without quercetin (100 mg (kg·bw)−1) for 16 weeks, and carotid plaques from patients with carotid stenosis are collected for histopathological examinations and molecular mechanism assays. Quercetin significantly alleviates atherosclerotic lesions and reduces lipid retention caused by HFD. Proteomic technology identified Gal­‐3 increased by HFD but lowered by quercetin. Furthermore, immunofluorescence and immunohistochemistry exhibit higher expressions of Gal‐3 and NLRP3 in carotid plaques and plaques from HFD‐fed mice, which are concurrently down‐regulated by quercetin. Similar to TD139, quercetin dramatically suppresses NLRP3 inflammasome activation in oxidized low‐density lipoprotein‐laden macrophages, and accordingly alleviates cellular steatosis and IL‐1β secretion, which is abolished by recombinant Gal‐3. Co‐immunoprecipitation shows Gal‐3 binding to NLRP3 promotes inflammasome activation. Conclusion Gal‐3 initiates inflammatory lesions by activating NLRP3 inflammasome which functions as a candidate target of quercetin exerting favorable anti‐atherogenic effects. The findings highlight a promising strategy for atherosclerosis prevention and treatment by naturally‐occurring quercetin.

Modulatory Properties of Food and Nutraceutical Components Targeting NLRP3 Inflammasome Activation

“…The same quercetin dosage described in the previous study has been applied for 16 days in high fat treated ApoE −/− mice to observe the potential reduction in atherosclerotic inflammation, where NLRP3 inflammasome is largely involved. In the study, an important decrease in pro-IL-1β and IL-1β was registered [ 68 ]. The effect of quercetin in reducing inflammasome activation has also been demonstrated for neurodegenerative models [ 69 ], since aging mice treated with 35 and 70 mg/kg (2.8 and 5.6 mg/kg HED) of quercetin for 4 weeks have shown a dose-dependent increase in the cognitive functions, together with an important reduction in NLRP3 activation factors expression by Western blot analysis.…”

The Potency of Moringa oleifera Lam. as Protective Agent in Cardiac Damage and Vascular Dysfunction

“…In addition, quercetin attenuates the pro-oxidants, such as MDA and superoxide ( Loke et al, 2010 ). Quercetin can also mitigate atherosclerotic inflammation through modulating galectin-3 (Gal-3)-pyrin domain-containing 3 (NLRP3) ( Li et al, 2021 ), and 5′adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NF-κB signaling pathway ( Zhang et al, 2020 ) inhibits lipid droplet formation by regulating proprotein convertase subtilisin/kexin type 9 (PCSK9), ATP-binding cassette sub-family G member 1 (ABCG1), and ATP-binding cassette transporter 1 (ABCAl) ( Li et al, 2018 ). Furthermore, quercetin can ameliorate atherosclerotic lesions by altering the gut microbiota and depressing atherogenic lipid metabolites ( Nie et al, 2019 ).…”

Macrophage Subsets and Death Are Responsible for Atherosclerotic Plaque Formation

“…As shown in Table 3 , the cholesterol crystal or ox-LDL is phagocytosed by macrophages, which facilitate NLRP3 inflammasome assembly and then activate caspase-1. Subsequently, activated caspase-1 cleaves pro-IL-1β to mature IL-1β, which induces inflammation and competes with cholesterol for access to the ABCA1, causing the retention of cholesterol to form foam cells ( 97 ). In addition, gasdermin D (GSDMD) could be cleaved by caspase-1 to N-terminal fragments (GSDMD-NT) and C-terminal fragments (GSDMD-CT) ( 133 ).…”