Abstract 056: Isolevuglandin-modified Phosphatidylethanolamines Generate Hypertension and Vascular Dysfunction in Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Arvind K Pandey ◽  
Hana A Itani ◽  
Liang Xiao ◽  
Annet Kirabo ◽  
Sergey Dikalov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Cells ◽  
Protein Modification ◽  
Low Dose ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Vascular Relaxation ◽  
Wild Type ◽  
Baseline Blood Pressure

Oxidative stress is an important contributor to hypertension. Our group has shown that oxidative stress generates isolevuglandins (isoLG) that modify proteins and that these isoLG-modified proteins seem to act as neoantigens to promote hypertension. In addition to proteins, isoLG can also modify phosphatidylethanolamines (PEs). IsoLG-modified PE (IsoLG-PE) can in turn activate immune cells via reactions with toll-like receptors and downstream pathways including NFκB. The role of isoLG-PE in hypertension has not yet been defined. We have previously shown that the enzyme N-acyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD) cleaves isoLG-PE, and mice lacking this enzyme have elevated cellular levels of isoLG-PE. To assess whether loss of NAPE-PLD and resulting increase in isoLG-PE contributes to hypertension, we infused wild type (WT) and NAPE-PLD -/- mice with low dose Ang II. We found baseline blood pressure was elevated in NAPE-PLD -/- mice compared to WT mice (128 ± 3 vs 111 ± 2 mmHg, p = 0.005) and that the increase in BP to low dose Ang II infusion (140 ng/kg/min) was augmented in NAPE-PLD -/- compared to WT mice (146 ± 9 vs 127 ± 4 mmHg, p=0.045). Endothelium-dependent vascular relaxation of the mesenteric arterioles to acetylcholine was impaired in NAPE-PLD -/- compared to WT mice (maximum relaxation of 43% ± 6% vs 53% ± 5%, p= 0.004), but endothelium-independent responses to sodium nitroprusside were similar in both groups (82% ± 2% in NAPE-PLD -/- mice vs 81% ± 4% in WT mice). Aortic adventitial collagen content by planimetry was likewise increased in NAPE-PLD -/- versus WT mice following low-dose Ang II. These studies in mice lacking NAPE-PLD suggest that in addition to exerting its effects via protein modification to form neo-antigens, the reaction of isoLG with PE and related phospholipids can augment hypertension, alter endothelium-dependent vasodilatation and promote vascular fibrosis.

scholarly journals Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging

2009 ◽  
Vol 296 (6) ◽  
pp. H1914-H1919 ◽  
Author(s):  
Mary L. Modrick ◽  
Sean P. Didion ◽  
Curt D. Sigmund ◽  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Wild Type ◽  
Very Old ◽  
Vascular Responses ◽  
Basilar Arteries ◽  
Old Mice ◽  
Cerebral Vascular

Vascular dysfunction occurs with aging. We hypothesized that oxidative stress and ANG II [acting via ANG II type 1 (AT1) receptors] promotes cerebral vascular dysfunction with aging. We studied young (5–6 mo), old (17–19 mo), and very old (23 ± 1 mo) mice. In basilar arteries in vitro, acetylcholine (an endothelium-dependent agonist) produced dilation in young wild-type mice that was reduced by ∼60 and 90% ( P < 0.05) in old and very old mice, respectively. Similar effects were seen using A23187, a second endothelium-dependent agonist. The vascular response to acetylcholine in very old mice was almost completely restored with tempol (a scavenger of superoxide) and partly restored by PJ34, an inhibitor of poly(ADP-ribose) polymerase (PARP). We used mice deficient in Mn-SOD (Mn-SOD+/−) to test whether this form of SOD protected during aging but found that age-induced endothelial dysfunction was not altered by Mn-SOD deficiency. Cerebral vascular responses were similar in young mice lacking AT1 receptors (AT1−/−) and wild-type mice. Vascular responses to acetylcholine and A23187 were reduced by ∼50% in old wild-type mice ( P < 0.05) but were normal in old AT1-deficient mice. Thus, aging produces marked endothelial dysfunction in the cerebral artery that is mediated by ROS, may involve the activation of PARP, but was not enhanced by Mn-SOD deficiency. Our findings suggest a novel and fundamental role for ANG II and AT1 receptors in age-induced vascular dysfunction.

Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia

2000 ◽  
Vol 278 (4) ◽  
pp. H1311-H1319 ◽  
Author(s):  
Wilhelm Kossenjans ◽  
Annie Eis ◽  
Rashmi Sahay ◽  
Diane Brockman ◽  
Leslie Myatt
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Human Placenta ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Vascular Responses ◽  
Before And After

Oxidative stress may increase production of superoxide and nitric oxide, leading to formation of prooxidant peroxynitrite to cause vascular dysfunction. Having found nitrotyrosine residues, a marker of peroxynitrite action, in placental vessels of preeclamptic and diabetic pregnancies, we determined whether vasoreactivity is altered in these placentas and treatment with peroxynitrite produces vascular dysfunction. The responses of diabetic, preeclamptic, and normal placentas to increasing concentrations of the vasoconstrictors U-46619 (10− 9–10− 7M) and ANG II (10− 9–10− 7M) and the vasodilators glyceryl trinitrate (10− 9–10− 7M) and prostacyclin (PGI2; 10− 8–10− 6M) were compared as were responses to these agents in normal placentas before and after treatment with 3.16 × 10− 4 M peroxynitrite for 30 min. Responses to both vasoconstrictors and vasodilators were significantly attenuated in diabetic and preeclamptic placentas compared with controls. Similarly, responses to U-46619, nitroglycerin, and PGI2, but not ANG II, were significantly attenuated following peroxynitrite treatment. The presence of nitrotyrosine residues confirmed peroxynitrite interaction with placental vessels. Overall, our data suggest that peroxynitrite formation is capable of attenuating vascular responses in the human placenta.

Abstract P618: Inactivation of Mitochondrial Deacetylase Sirt3 Promotes Vascular Oxidative Stress, Increases Endothelial Dysfunction and Exacerbates Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna E Dikalova ◽  
Roman Uzhachenko ◽  
Hana A Itani ◽  
David G Harrison ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Fold Increase ◽  
Organ Damage ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Oxidative Stress

Endothelial dysfunction is associated with aging, diabetes, hyperlipidemia, obesity and these risk factors affect the expression and activity of the mitochondrial deacetylase Sirt3. Sirt3 activates major antioxidant SOD2 by deacetylation of specific lysine residues and Sirt3 depletion increases oxidative stress. We hypothesized that loss of vascular Sirt3 increases endothelial dysfunction, promotes hypertension and end organ damage. The role of vascular Sirt3 was studied in wild-type C57Bl/6J mice and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ) using angiotensin II model of hypertension (Ang II, 0.7 mg/kg/day). Western blot showed 30% reduction of vascular Sirt3 and 2-fold increase in SOD2 acetylation in Ang II-infused WT mice. We have tested if ex vivo treatment of aorta with Sirt3 activator resveratrol improves endothelial function. Indeed, ex vivo incubation with resveratrol (10 μM) significantly reduced SOD2 acetylation, diminished mitochondrial O 2 and increased endothelial NO to normal level while Sirt3-inactive analog dihydroresveratrol had no effect. Specific role of vascular Sirt3 was studied in Smc Sirt3 KO mice by crossing floxed Sirt3 mice with mice carrying gene for inducible cre in the vascular smooth muscle. Sirt3 deletion exacerbates hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increases mortality in Ang II-infused Smc Sirt3 KO mice (60% vs 10% in wild-type) associated with severe edema and aortic aneurysm (100% vs 20% in wild-type). Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. Indeed, Ang II infusion increased vascular O 2 by 2-fold and reduced endothelial NO by 2-fold. Interestingly, Ang II infusion in Smc Sirt3 KO mice caused severe vascular oxidative stress (3-fold increase in O 2 ) and exacerbated endothelial dysfunction (4-fold decrease in NO). These data indicate that reduced vascular Sirt3 activity occurs in hypertension and this promotes vascular oxidative stress, increases endothelial dysfunction, exacerbates hypertension, increases end-organ-damage and mortality. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

scholarly journals Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain

2012 ◽  
Vol 113 (2) ◽  
pp. 184-191 ◽  
Author(s):  
Sophocles Chrissobolis ◽  
Botond Banfi ◽  
Christopher G. Sobey ◽  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Minor Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Beds ◽  
A Minor

Angiotensin II (Ang II) promotes vascular disease through several mechanisms including by producing oxidative stress and endothelial dysfunction. Although multiple potential sources of reactive oxygen species exist, the relative importance of each is unclear, particularly in individual vascular beds. In these experiments, we examined the role of NADPH oxidase (Nox1 and Nox2) in Ang II-induced endothelial dysfunction in the cerebral circulation. Treatment with Ang II (1.4 mg·kg−1·day−1 for 7 days), but not vehicle, increased blood pressure in all groups. In wild-type (WT; C57Bl/6) mice, Ang II reduced dilation of the basilar artery to the endothelium-dependent agonist acetylcholine compared with vehicle but had no effect on responses in Nox2-deficient (Nox2−/y) mice. Ang II impaired responses to acetylcholine in Nox1 WT (Nox1+/y) and caused a small reduction in responses to acetylcholine in Nox1-deficient (Nox1−/y) mice. Ang II did not impair responses to the endothelium-independent agonists nitroprusside or papaverine in either group. In WT mice, Ang II increased basal and phorbol-dibutyrate-stimulated superoxide production in the cerebrovasculature, and these increases were abolished in Nox2−/y mice. Overall, these data suggest that Nox2 plays a relatively prominent role in mediating Ang II-induced oxidative stress and cerebral endothelial dysfunction, with a minor role for Nox1.

scholarly journals Syntaxin-17-Dependent Mitochondrial Dynamics is Essential for Protection Against Oxidative-Stress-Induced Apoptosis

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 522 ◽  
Author(s):  
Wang ◽  
Xiao ◽  
Huang ◽  
Liu
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Autophagic Flux ◽  
Wild Type ◽  
Dual Roles ◽  
Defective Mutant ◽  
U2os Cells ◽  
Induced Apoptosis

In this study, cell death induced by the oxidant tert-butylhydroperoxide (tBH) was observed in U2OS cells; this phenotype was rescued by Syntaxin 17 (STX17) knockout (KO) but the mechanism is unknown. STX17 plays dual roles in autophagosome–lysosome fusion and mitochondrial fission. However, the contribution of the two functions of STX17 to apoptosis has not been extensively studied. Here, we sought to dissect the dual roles of STX17 in oxidative-stress-induced apoptosis by taking advantage of STX17 knockout cells and an autophagosome–lysosome fusion defective mutant of STX17. We generated STX17 knockout U2OS cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and the STX17 knockout cells were reconstituted with wild-type STX17 and its autophagosome–lysosome fusion defective mutant. Autophagy was assessed by autophagic flux assay, Monomer red fluorescent protein (mRFP)–GFP–LC3 assay and protease protection assay. Golgi, endoplasmic reticulum (ER)/ER–Golgi intermediate compartment (ERGIC) and mitochondrial dynamics were examined by staining the different indicator proteins. Apoptosis was evaluated by caspase cleavage assay. The general reactive oxygen species (ROS) were detected by flow cytometry. In STX17 complete knockout cells, sealed autophagosomes were efficiently formed but their fusion with lysosomes was less defective. The fusion defect was rescued by wild-type STX17 but not the autophagosome–lysosome fusion defective mutant. No obvious defects in Golgi, ERGIC or ER dynamics were observed. Mitochondria were significantly elongated, supporting a role of STX17 in mitochondria fission and the elongation caused by STX17 KO was reversed by the autophagosome–lysosome fusion defective mutant. The clearance of protein aggregation was compromised, correlating with the autophagy defect but not with mitochondrial dynamics. This study revealed a mixed role of STX17 in autophagy, mitochondrial dynamics and oxidative stress response. STX17 knockout cells were highly resistant to oxidative stress, largely due to the function of STX17 in mitochondrial fission rather than autophagy.

scholarly journals The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

2021 ◽  
Vol 22 (5) ◽  
pp. 2578
Author(s):  
Trim Lajqi ◽  
Christian Marx ◽  
Hannes Hudalla ◽  
Fabienne Haas ◽  
Silke Große ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Low Dose ◽  
Innate Immune ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Atp Production ◽  
Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

scholarly journals Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

2021 ◽  
Vol 22 (3) ◽  
pp. 1296
Author(s):  
Yue Ruan ◽  
Subao Jiang ◽  
Adrian Gericke
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Therapeutic Strategies ◽  
Vision Impairment ◽  
Age Related Macular Degeneration ◽  
Oxygen Species ◽  
Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

Dyslipdemia induced by chronic low dose co-exposure to lead, cadmium and manganese in rats: the role of oxidative stress

2017 ◽  
Vol 53 ◽  
pp. 199-205 ◽  
Author(s):  
Olusola Olalekan Oladipo ◽  
Joseph Olusegun Ayo ◽  
Suleiman Folorunsho Ambali ◽  
Bisalla Mohammed ◽  
Tanang Aluwong
Keyword(s):  
Oxidative Stress ◽  
Low Dose

scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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