Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome

Wang, Wei; Wu, Qiuhong; Sui, Yong; Wang, Yan; Qiu, Xiu

doi:10.1016/j.biopha.2016.11.134

Cited by 73 publications

(38 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, NOX4 has been reported to regulate NLRP3 inflammasome activation in human umbilical vein endothelial cells under high-glucose environment and to modulate TXNIP [62]. Although NOX2 did not regulate NLRP3 or TXNIP in the umbilical vein endothelial cells [62], NOX2 deletion attenuated NLRP3 induction in the cerebral cortex of mice after ischemic stroke [63], as we observed after TBI. The reason for the divergent effects is not clear, but it could suggest that NOX isoform regulation of NLRP3 inflammasome activation may be tissue- and/or context specific.…”

Section: Discussionmentioning

confidence: 56%

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

Merry

Wang

Dhandapani

et al. 2017

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

show abstract

Section: Discussionmentioning

confidence: 56%

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

Merry

Wang

Dhandapani

et al. 2017

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Wang et al. reported that rutin reduced NLRP3, ASC, and IL‐1β expression in HUVECs and improved endothelial functions by suppressing NLRP3 and caspase‐1 expression in the thoracic aorta of the diabetic rats . These results indicate that rutin ameliorates inflammatory endothelial dysfunction by inhibiting the NLRP3 inflammasome pathway during high‐glucose stress, both in vitro and in vivo.…”

Section: Flavonoids and Inflammasome Activationmentioning

confidence: 93%

Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses

2018

Molecular Nutrition Food Res

View full text Add to dashboard Cite

Inflammation is an innate immune response to noxious stimuli to protect the body from pathogens. Inflammatory responses consist of two main steps: priming and triggering. In priming, inflammatory cells increase expressions of inflammatory molecules, while in triggering, inflammasomes are activated, resulting in cell death and pro-inflammatory cytokine secretion. Inflammasomes are protein complexes comprising intracellular pattern recognition receptors (PRRs) (e.g., nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2), and caspases-4/5/11) and pro-caspase-1 with or without a bipartite adaptor molecule ASC. Inflammasome activation induces pyroptosis, inflammatory cell death, and stimulates caspase-1-mediated secretion of interleukin (IL)-1b and IL-18. Flavonoids are secondary metabolites found in various plants and are considered as critical ingredients promoting health and ameliorating various disease symptoms. Anti-inflammatory activity of flavonoids and underlying mechanisms have been widely studied. This review introduces current knowledge on different types of inflammasomes and their activation during inflammatory responses and discusses recent studies regarding anti-inflammatory roles of flavonoids as suppressors of inflammasomes in inflammatory conditions. Understanding the regulatory effects of flavonoids on inflammasome activation will increase our knowledge of flavonoid-mediated anti-inflammatory activity and provide new insights into the development of flavonoid preparations to prevent and treat human inflammatory diseases.

show abstract

“…Other studies support an interaction between NLRP3 inflammasome and Nox expression and activity. Nox4 inhibition prevents ROS generation and decreases protein expression of NLRP3, caspase-1 and IL-1β in endothelial cells stimulated with high glucose (Wang et al, 2017). Decreased NLRP3 inflammasome activation associated with reduced Nox4 expression and ROS generation was also reported in rat cardioblasts stimulated with TNF-α and submitted to hypoxia (Chen et al, 2018).…”

Section: Discussionmentioning

confidence: 67%

Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes

et al. 2020

View full text Add to dashboard Cite

Introduction NLRP3 inflammasome is a molecular platform of innate immune system that regulates the inflammatory response through the activation of caspase‐1 and IL‐1β. It can be activated by several ligands, for example, mitochondrial DNA (mDNA). Some studies have shown that circulating mDNA is increased in patients with diabetes and play a role in the development of the disease; however, its role in vascular changes is still unknown. In this sense, we tested the hypothesis that mDNA contributes to vascular inflammatory/oxidative processes associated to type 1 diabetes (T1D) via NLRP3 inflammasome activation. Methods Wild‐type and NLRP3‐deficient (NLRP3−/−) mice were treated with vehicle (Veh) or streptozotocin (40 mg/kg) (T1D) for 5 days. Vascular reactivity was determined in mesenteric arteries. Caspase‐1 and IL‐1β expression were evaluated by western blot. Pancreatic mDNA was extracted from control (cmDNA) and diabetic animals (dmDNA) for endothelial cells stimulation. ROS generation was determined by chemiluminescence. Hydrogen peroxide (H2O2) production and calcium influx were determined by fluorescence. Data are presented as mean ± standard error of the mean. Results Diabetes increased vascular caspase‐1 and IL‐1β activation [arbitrary units (a.u.), 1.2±0.1 vs. 0.8±0.1; 4.8±1.1 vs. 0.8±0.5 vs. the Veh, respectively, p <0.05]. However, this activation was attenuated in T1D NLRP3−/−. Mesenteric arteries from T1D exhibited decreased ACh‐induced vasodilatation vs. Veh [(Emax), 46.6±4.0 vs. 91.5±2.8, n=4–5, p<0.05], which was not observed in T1D NLRP3−/−. The NLRP3 inhibitor MCC950 acutely improved endothelium‐dependent vasodilation in T1D [(Emax), 62.5±3.8 vs. 85.6±3.7, n=4–5, p<0.05]. ROS generation [(Relative luminescence unit, RLU), 1.5×107±2.3 vs. 48.9×103±1.1, n=4–5, p<0.05] as well as H2O2 production [(Relative fluorescence unit, RFU), 1082±242.6 vs. 232.0±42.8, n=4–5, p<0.05] were lower in mesenteric bed from T1D NLRP3−/− than T1D. Only incubation with dmDNA reduced ACh‐induced vasodilation [(Emax), 48.4 ± 4.1 vs. 90.7 ± 3.4, n=4–5, p<0.05], which was attenuated by the presence of an antioxidant [(Emax), 48.4 ± 4.1 vs. 71.5 ± 3.1, n=4–5, p<0.05]. Similarly, only LPS‐primed cells incubated with dmDNA had significant NLRP3 activation (caspase‐1 and IL‐1β activation, respectively) [(u.a.), 1.6 ± 0.2 vs. 0.9 ± 0.1; and 1.6 ± 0.2 vs. 1.0 ± 0.1, n=4–5, p<0.05]. The dmDNA induced in a time‐dependent way both calcium influx and ROS generation in endothelial cells, being the last reversed by the presence of an antioxidant. Likewise, T1D patients had increased circulating mDNA vs. healthy volunteers and also higher NLRP3 serum expression, and caspase‐1/IL‐1β activation. Conclusion The T1D increases mDNA release which in turn stimulates increased calcium influx, induces ROS generation, and triggers vascular NLRP3 inflammasome activation contributing to inflammatory response and endothelial dysfunction in diabetes. Support or Funding Information Financial Support: FAPESP and CAPES. Ethics Committee number (026/2015)...

show abstract

Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome

Cited by 73 publications

References 29 publications

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses

Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes

Contact Info

Product

Resources

About