Aging-associated metabolic disorder induces Nox2 activation and oxidative damage of endothelial function

Fan, Lampson M.; Cahill-Smith, Sarah; Geng, Li; Du, Junjie; Brooks, Gavin; Li, Jianmei

doi:10.1016/j.freeradbiomed.2017.05.008

Cited by 58 publications

(48 citation statements)

References 30 publications

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“…We demonstrated that ASM down‐regulation indeed inhibited the production of O 2 − , which was mainly derived from ceramide and NADPH oxidase in PA‐induced RAECs. This is consistent with the reports that NADPH oxidase activation damages endothelial function and induces insulin resistance , and PA stimulates the production of ROS through activating NADPH oxidases . Our previous study also demonstrated that ASM mediated the aggregation of membrane raft, forming NADPH oxidase‐mediated O 2 −· production in coronary arterial endothelial cells .…”

Section: Discussionsupporting

confidence: 92%

“…We further explored the isoforms of NADPH oxidases to mediate the oxidative stress of ASM in RAECs. Among Nox isoforms, Nox1, 2 and 4 are expressed in vascular endothelial cells , and Nox2 and Nox4 are highly expressed in vascular endothelial cells , which were activated by PA in the current study. It has been shown that ASM and ceramide could activate the Nox2 isoform in non‐muscle cells through enhancing phosphorylation of p47 phox 44 .…”

Section: Discussionsupporting

confidence: 50%

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Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Jin

et al. 2018

Basic Clin Pharma Tox

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Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in patients with type 2 diabetes. Acid sphingomyelinase (ASM) is a soluble glycoprotein which plays a vital role in the development and progression of various diseases such as cardiovascular and metabolic diseases. However, it remains unknown if ASM regulates insulin resistance in vascular endothelial cells in type 2 diabetes. ASM down-regulation with gene silencing and selective inhibitor amitriptyline was used in the rat aortic endothelial cells (RAECs) treated with palmitic acid (PA), a common saturated free fatty acid, which is thought to be the major cause of insulin resistance. It was shown that ASM down-regulation increased glucose uptake and glucose transporter-4 (Glut4) expression and reversed the phosphorylation of pIRS-1-ser307 and AKT-ser473 via ceramide, consequently resulting in the decrease of the production of endothelial nitric oxide synthase (eNOS) and nitric oxide in PA-induced RAECs. We further found that ASM down-regulation blocked the Nox2- and Nox4-dependent superoxide (O ) generation, which regulated glucose metabolism in RAECs during PA stimulation. In vivo, amitriptyline relieved the vasodilatory response to acetylcholine and restored the level of ceramide, Nox2 and Nox4 in the aorta endothelium of high-fat diet-fed rats following an injection of streptozotocin. Taken together, these results suggest that ASM down-regulation can improve endothelial insulin resistance which is attributed to inhibiting redox signalling in RAECs. Thus, these data support the idea that ASM is a promising clinical biomarker and potential therapeutic target for diabetic vascular complication.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 50%

Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Jin

et al. 2018

Basic Clin Pharma Tox

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“…In VSMCs, Nox4 downregulation induces senescence [182], while in ECs, reduced Nox4 expression inhibits senescence [183]. Nox2 downregulation was also associated with reduced EC senescence [184]. A more comprehensive review of the role of NADPH oxidases in vascular senescence can be found in our recent review [155].…”

Section: Cigarette Smoke and Nicotine In Senescencementioning

confidence: 93%

Nicotine in Senescence and Atherosclerosis

Centner

Bhide²,

Salazar

2020

Cells

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Cigarette smoke is a known exacerbator of age-related pathologies, such as cardiovascular disease (CVD), atherosclerosis, and cellular aging (senescence). However, the role of nicotine and its major metabolite cotinine is yet to be elucidated. Considering the growing amount of nicotine-containing aerosol use in recent years, the role of nicotine is a relevant public health concern. A number of recent studies and health education sites have focused on nicotine aerosol-induced adverse lung function, and neglected cardiovascular (CV) impairments and diseases. A critical review of the present scientific literature leads to the hypothesis that nicotine mediates the effects of cigarette smoke in the CV system by increasing MAPK signaling, inflammation, and oxidative stress through NADPH oxidase 1 (Nox1), to induce vascular smooth muscle cell (VSMC) senescence. The accumulation of senescent VSMCs in the lesion cap is detrimental as it increases the pathogenesis of atherosclerosis by promoting an unstable plaque phenotype. Therefore, nicotine, and most likely its metabolite cotinine, adversely influence atherosclerosis.

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“…Mitochondrial targeted antioxidants decrease aortic ICAM in old mice (Zinovkin et al., ), and in rat endothelial cells scavenging of mitochondrial ROS attenuates NFκB activity and inflammatory cytokine production (Ungvari et al., ). The age‐related increase in aortic VCAM is dependent on the NAPDH oxidase subunit Nox2 (Fan et al., ). Leucocyte recruitment to arteries is greater in 9‐month‐old mice that overexpress p22phox in smooth muscle compared with 9‐month‐old control animals (Wu et al., ).…”

Section: Interventions To Ameliorate Age‐related Inflammation and Artmentioning

confidence: 99%

“…Mitochondrial targeted antioxidants decrease aortic ICAM in old mice (Zinovkin et al, 2014), and in rat endothelial cells scavenging of mitochondrial ROS attenuates NF B activity and inflammatory cytokine production (Ungvari et al, 2007). The age-related increase in aortic VCAM is dependent on the NAPDH oxidase subunit Nox2 (Fan et al, 2017).…”

Section: Role Of Ros and Antioxidant Interventionsmentioning

confidence: 99%

Inflammation as a mediator of arterial ageing

Trott

Fadel

2019

Experimental Physiology

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New Findings What is the topic of this review?This review summarizes and synthesizes what is known about the contribution of inflammation to age‐related arterial dysfunction. What advances does it highlight?This review details observational evidence for the relationship of age‐related inflammation and arterial dysfunction, insight from autoimmune inflammatory diseases and their effects on arterial function, interventional evidence linking inflammation and age‐related arterial dysfunction, insight into age‐related arterial inflammation from preclinical models and interventions to ameliorate age‐related inflammation and arterial dysfunction. Abstract Advanced age is a primary risk factor for cardiovascular disease, the leading cause of death in the industrialized world. Two major components of arterial ageing are stiffening of the large arteries and impaired endothelium‐dependent dilatation in multiple vascular beds. These two alterations are major contributors to the development of overt cardiovascular disease. Increasing inflammation with advanced age is likely to play a role in this arterial dysfunction. The purpose of this review is to synthesize what is known about inflammation and its relationship to age‐related arterial dysfunction. This review discusses both the initial observational evidence for the relationship of age‐related inflammation and arterial dysfunction and the evidence that inflammatory autoimmune diseases are associated with a premature arterial ageing phenotype. We next discuss interventional and mechanistic evidence linking inflammation and age‐related arterial dysfunction in older adults. We also attempt to summarize the relevant evidence from preclinical models. Lastly, we discuss interventions in both humans and animals that have been shown to ameliorate age‐related arterial inflammation and dysfunction. The available evidence provides a strong basis for the role of inflammation in both large artery stiffening and impairment of endothelium‐dependent dilatation; however, the specific inflammatory mediators, the initiating factors and the relative importance of the endothelium, smooth muscle cells, perivascular adipose tissue and immune cells in arterial inflammation are not well understood. With the expansion of the ageing population, ameliorating age‐related arterial inflammation represents an important potential strategy for preserving vascular health in the elderly.

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Aging-associated metabolic disorder induces Nox2 activation and oxidative damage of endothelial function

Cited by 58 publications

References 30 publications

Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Nicotine in Senescence and Atherosclerosis

Inflammation as a mediator of arterial ageing

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