Role of iNOS in Insulin Resistance and Endothelial Dysfunction

Aggarwal, Hobby; Kanuri, Babunageswararao; Dikshit, Madhu

doi:10.1007/978-981-13-8273-4_21

Cited by 9 publications

(5 citation statements)

References 161 publications

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“…iNOS −/− mice are however protected against LPS-induced in ammation and the associated metabolic perturbations [29][30][31]. iNOS −/− mice were insulin resistant and dyslipidemic on chow, LFD, and HFD diets, which was improved substantially by nitrite supplementation [24,25,27,44]. To investigate further the role of gut bacteria in metabolic perturbations in iNOS −/− mice we checked the microbial diversity in fecal samples.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria And Metabolites Remediate Insulin Resistance In INOS Knockout Mice

Aggarwal

Pathak

Singh

et al. 2021

Preprint

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Background: Inducible nitric oxide synthase (iNOS) has emerged as a crucial regulator of host metabolism and gut microbiota activity. The present study examines the role of the gut microbiome in determining host metabolic functions in absence of iNOS.Results: Insulin resistant and dyslipidemic iNOS-/- mice displayed reduced microbial diversity, with a higher relative abundance of the gram-positive bacteria, Allobaculum and Bifidobacterium, and altered serum metabolites linked with the metabolic dysregulation. Vancomycin, which largely depletes gram-positive bacteria, reversed the insulin resistance (IR), dyslipidemia, and related metabolic abnormalities in iNOS-/- mice. Such correction in metabolic markers was accompanied by reduced the expression of genes involved in fatty acid synthesis in liver and adipose tissue, decreased lipid uptake by adipose tissue and enhanced lipid efflux by liver and intestine. Rescue of IR in vancomycin treated iNOS-/- mice was associated with the alterations in the select serum metabolites such as 10-hydroxydecanoate, indole-3-ethanol, allantoin, hippurate, sebacic acid, aminoadipate, and ophthalmate, along with improvement in phosphatidylethanolamine to phosphatidylcholine (PE/PC) ratio.Conclusions: Vancomycin-mediated depletion of gram-positive bacteria negates the detrimental metabolic effect, dyslipidemia and IR, observed in iNOS-/- mice.

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Section: Discussionmentioning

confidence: 99%

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria And Metabolites Remediate Insulin Resistance In INOS Knockout Mice

Aggarwal

Pathak

Singh

et al. 2021

Preprint

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“…50 For instance, augmented synthesis of NO by increased expression of eNOS has been suggested to be a cellular mechanism to protect endothelial function 51 ; while increased NO production by iNOS has been associated with a pro-inflammatory state and oxidative stress. 52 Here, we showed higher ROS as well as nitrotyrosine levels in aortas from PP-HCD mice, which also had higher vascular iNOS levels, suggesting that increased iNOS expression in the PP-HCD females may reduce NO bioavailability by increasing vascular oxidative/nitrosative stress. In addition, aortas from PP-HCD groups had lower SOD-1 levels compared with the PP-CD group.…”

Section: Discussionmentioning

confidence: 47%

A High Cholesterol Diet During Late Pregnancy Impairs Long-Term Maternal Vascular Function in Mice

Sáez

Pageé

Kirschenman

et al. 2023

ATVB

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BACKGROUND: Gestational dyslipidemia is associated with pregnancy complications including preeclampsia. However, whether gestational dyslipidemia leads postpartum vascular dysfunction, which could increase the risk for cardiovascular complications later in life, is not known. Here, we aimed to determine whether a gestational dyslipidemia affects postpartum vascular health and induces early signs of atherosclerosis. METHODS: Pregnant C57BL/6 mice received a high cholesterol diet or control diet from gestational day 13.5 until term. After delivery, all mice received the control diet for ≈3 months postpartum (PP). Age-matched nulliparous females were on the same diets for equal periods. After 3 months, all mice were euthanized, serum was collected, and aortas were isolated to assess vascular function (wire myography) and markers of oxidative stress and early atherosclerosis. RESULTS: PP-high cholesterol diet females had increased circulating cholesterol levels compared with PP-control diet mice, without effect of the diet in nulliparous mice. Methacholine-induced vasodilation was impaired, and nitric oxide contribution reduced, by the high cholesterol diet in aortas of PP mice, but not in nulliparous mice. Exposure to oxidized low-density–protein cholesterol further impaired methylcholine-induced vasodilation in PP-high cholesterol diet aortas only. Compared with PP-control diet mice, aortic inducible nitric oxide synthase expression, reactive oxygen species and nitrotyrosine levels were increased in aortas from PP-high cholesterol diet mice. No differences in aortic lipid deposition and macrophage infiltration were found. CONCLUSIONS: Exposure to a high cholesterol diet in pregnancy impairs vascular function postpartum. Our results support the hypothesis that gestational dyslipidemia impacts maternal vascular function after pregnancy, which could potentially predispose these women to future cardiovascular complications.

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“…iNOS −/− mice are, however, protected against LPS-induced inflammation and the associated metabolic perturbations ( Chauhan et al., 2003 ; Carvalho-Filho et al., 2006 ; House et al., 2012 ). iNOS −/− mice were insulin resistant and dyslipidemic on chow, LFD, and HFD diets, which was improved substantially by nitrite supplementation ( Kanuri et al., 2017 ; Aggarwal et al., 2019 ; Pathak et al., 2019 ; Aggarwal et al., 2020 ). To investigate further the role of gut bacteria in metabolic perturbations in iNOS −/− mice, we checked the microbial diversity in fecal samples.…”

Section: Discussionmentioning

confidence: 99%

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria and Metabolites Remediates Insulin Resistance in iNOS Knockout Mice

Aggarwal

Pathak

Singh

et al. 2022

Front. Cell. Infect. Microbiol.

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The role of oxidative and nitrosative stress has been implied in both physiology and pathophysiology of metabolic disorders. Inducible nitric oxide synthase (iNOS) has emerged as a crucial regulator of host metabolism and gut microbiota activity. The present study examines the role of the gut microbiome in determining host metabolic functions in the absence of iNOS. Insulin-resistant and dyslipidemic iNOS−/− mice displayed reduced microbial diversity, with a higher relative abundance of Allobaculum and Bifidobacterium, gram-positive bacteria, and altered serum metabolites along with metabolic dysregulation. Vancomycin, which largely depletes gram-positive bacteria, reversed the insulin resistance (IR), dyslipidemia, and related metabolic anomalies in iNOS−/− mice. Such improvements in metabolic markers were accompanied by alterations in the expression of genes involved in fatty acid synthesis in the liver and adipose tissue, lipid uptake in adipose tissue, and lipid efflux in the liver and intestine tissue. The rescue of IR in vancomycin-treated iNOS−/− mice was accompanied with the changes in select serum metabolites such as 10-hydroxydecanoate, indole-3-ethanol, allantoin, hippurate, sebacic acid, aminoadipate, and ophthalmate, along with improvement in phosphatidylethanolamine to phosphatidylcholine (PE/PC) ratio. In the present study, we demonstrate that vancomycin-mediated depletion of gram-positive bacteria in iNOS−/− mice reversed the metabolic perturbations, dyslipidemia, and insulin resistance.

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Role of iNOS in Insulin Resistance and Endothelial Dysfunction

Cited by 9 publications

References 161 publications

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria And Metabolites Remediate Insulin Resistance In INOS Knockout Mice

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria And Metabolites Remediate Insulin Resistance In INOS Knockout Mice

A High Cholesterol Diet During Late Pregnancy Impairs Long-Term Maternal Vascular Function in Mice

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria and Metabolites Remediates Insulin Resistance in iNOS Knockout Mice

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