Abstract 066: Cyclooxygenase-depended Signaling Via Thromboxane Prostanoid Receptors Mediates Endothelin-i Induced Ros Generation In Mesenteric Resistance Vessels From Mice Infused With Angiotensin Ii

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Christopher S Wilcox ◽  
Cheng Wang ◽  
Dan Wang
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Ros Generation ◽  
Oxygen Species ◽  
Ang Ii ◽  
Wild Type ◽  
Prostanoid Receptors ◽  
Resistance Vessels ◽  
Cox 2 ◽  
Cox 1

Background: Angiotensin II (Ang II) increases reactive oxygen species (ROS) and contractions to thromboxane and endothelin-1 (ET-1). Therefore, we tested the hypothesis that cyclooxygenase (COX) and/or thromboxane-prostanoid receptors (TP-Rs) mediate enhanced ROS generations with ET-1 in Ang II-infused mice. Methods: ROS was assessed by urinary 8-isoprotane(8-Iso) excretion and ethedium : dihydroetheldium (DHE) in mesenteric resistance arterioles (MRAs) from wild type (+/+) and littermate COX-1 -/- or TP-R -/- mice infused with vehicle or angiotensin II (Ang II, 400 ng/kg/min for 14 days) (n=6/ group, mean ±SEM). Results: Ang II infusion increased excretion (ng/mg creatine) of TxB 2 (1.3±0.1±1.0±0.1 in COX-1 +/+ mice and 1.9±0.1 vs 1.2±0.1 in TP-R +/+ mice, all P<0.05) and 8-Iso (2.1±0.2 vs 1.4±0.1 in COX-1 +/+ mice and 2.2±0.1 vs 1.4±0.2 in TP-R +/+ mice, all P<0.05) but not in COX-1 -/- or TP-R -/- mice. Ang II enhanced ROS generation (Δunit) with 10 -7 M ET-1 in MRAs from both +/+ mouse genotypes (1.7±0.2 vs 0.1±0.1 in COX-1 +/+ mice and 3.2±0.3 vs 0.1±0.1 in TP-R +/+ mice, all P<0.01). However, this increase in ROS was fully prevented in TP-R-/- mouse vessels (0.3±0.2 vs 0.2±0.1, NS) and in COX-1 +/+ mouse vessels after combined blockade of COX-1( 10 -5 M SC-560) and -2 (paracoxib 10 -5 M) (0.2±0.1 vs 0.1±0.1, NS) and in COX-1 -/- mouse vessels after paracoxib (0.2±0.1 vs 0.2±0.2, NS). Increased ROS generation was only partially prevented in COX-1 -/- mouse vessels (0.5±0.1 vs 0.2±0.2, P<0.05) or in COX-1 +/+ mouse vessels after blockade of COX-1 ( 0.7±0.1 vs 0.1±0.1, NS) or COX-2 (1.0±0.1 vs 0.1±0.1,P<0.05). Conclusions: Increased ROS generation with ET-1 in microvessels from Ang II infused mice depends on products of both COX-1 and -2 that activate TP-Rs. Thus, combined blockade of COX-1 and -2 or TP-Rs may prevent vascular ROS and its many complications during increased Ang II and ET-1, such as hypertension, hypoxia or shock.

Upregulation of cortical COX-2 in salt-sensitive hypertension: role of angiotensin II and reactive oxygen species

2008 ◽  
Vol 294 (2) ◽  
pp. F385-F392 ◽  
Author(s):  
Edgar A. Jaimes ◽  
Ming-Sheng Zhou ◽  
Damien D. Pearse ◽  
Leopold Puzis ◽  
Leopoldo Raij
Keyword(s):  
Reactive Oxygen Species ◽  
Urinary Excretion ◽  
Reactive Oxygen ◽  
Fold Increase ◽  
Receptor Blocker ◽  
Ros Generation ◽  
Oxygen Species ◽  
Ang Ii ◽  
Salt Diet ◽  
Cox 2

Salt-sensitive (SS) hypertension is a vascular diathesis characterized by reduced cardiovascular and renal nitric oxide bioavailability and local upregulation of ANG II. We have demonstrated that rats infused with ANG II manifest increased cortical cyclooxygenase (COX)-2 expression and activity via NADPH oxidase-derived reactive oxygen species (ROS). In the present studies we used Dahl salt-sensitive (DS) rats to test the hypothesis that hypertensive SS rats have increased cortical COX-2 upregulation, which is mediated by ANG II and ROS. DS rats were placed on either a normal-salt diet (0.5% NaCl) or a high-salt diet (4% NaCl) for 6 wk and treated with either the ANG II type 1 (AT1) receptor blocker candesartan (Can, 10 mg·kg−1·day−1) or the SOD mimetic tempol (1 mmol/l). Hypertensive SS rats had a twofold increase in the cortical expression of COX-2 as assessed by Western blot. These changes in COX-2 expression were accompanied by a 10-fold increase in COX-2 mRNA expression and a 2-fold increase in the urinary excretion of PGE2. Treatment with either the AT1 receptor blocker Can or the SOD mimetic tempol did not reduce blood pressure but resulted in significant reductions in the cortical expression of COX-2 and the urinary excretion of PGE2. In conclusion, we have demonstrated that local activation of the renin-angiotensin system, via increased ROS generation, mediates COX-2 upregulation in hypertensive SS rats. These studies unveil novel mechanistic pathways that may play a role in the pathogenesis of hypertensive renal injury.

scholarly journals Tubuloglomerular feedback is decreased in COX-1 knockout mice after chronic angiotensin II infusion

2010 ◽  
Vol 298 (4) ◽  
pp. F1059-F1063 ◽  
Author(s):  
Magali Araujo ◽  
William J. Welch
Keyword(s):  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Renal Cortex ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Hypertension ◽  
Genetic Deletion ◽  
Cox 2 ◽  
Cox 1

Prostaglandins (PGs), produced by two isoforms of cyclooxygenase (COX), COX-1 and COX-2, are important modulators of renal hemodynamics. COX-1 and COX-2 are expressed in the kidney often at distinct sites. Thromboxane (TxA2), PGE2, and prostacyclin (PGI2) are the major PGs in the renal cortex of mice. Acute infusion of the vasoconstrictor ANG II increases COX-2-dependent PGE2 and PGI2. COX-2 is primarily expressed in the macula densa (MD), where several PG synthases are also expressed. We previously showed that MD COX-2 products modulate tubuloglomerular feedback (TGF) in the rat. Genetic deletion of COX-1 enhances COX-2 production of PGs, decreases renal and urinary PGs, and attenuates ANG II-induced hypertension. The present study tested the effects of chronic ANG II infusion on TGF in COX-1 knockout (KO) mice. Basal TGF was similar in COX-1 KO and wild-type (WT) mice. Chronic ANG II infusion increased TGF in WT mice (WT: 9.3 ± 0.7 vs. WT + ANG II: 12.2 ± 1.6 mmHg, P < 0.02). However, chronic ANG II decreased TGF in COX-1 KO mice (KO: 11.4 ± 1.1 vs. KO + ANG II: 8.3 ± 0.6 mmHg, P < 0.01). Pretreatment with the COX-2 inhibitor SC-58,236 in COX-1 KO mice prevented the ANG II-associated reduction in TGF (11.4 ± 1.0 vs. 11.5 ± 0.28 mmHg, not significant). Excretion of 6-keto-PGF2α, the metabolite of PGI2, was increased by ANG II infusion, whereas excretion of TxB2, the stable metabolite of TxA2, was not changed. ANG II infusion increased mean arterial pressure similarly in both WT and KO mice (WT: 93 ± 2 vs. KO: 92 ± 3 mmHg), but not in KO mice pretreated with SC-58,236 (85 ± 2 mmHg). This study shows that COX-1-generated PGs partially mediate ANG II increases in TGF and that COX-2 PGs offset that effect.

scholarly journals COX-1-derived PGE2 and PGE2 type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca2+ influx in the subfornical organ

2013 ◽  
Vol 305 (10) ◽  
pp. H1451-H1461 ◽  
Author(s):  
Gang Wang ◽  
Pallabi Sarkar ◽  
Jeffrey R. Peterson ◽  
Josef Anrather ◽  
Joseph P. Pierce ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Reactive Oxygen ◽  
Subfornical Organ ◽  
Prostaglandin E ◽  
Oxygen Species ◽  
Ang Ii ◽  
Cox 1

Regulation of blood pressure by angiotensin II (ANG II) is a process that involves the reactive oxygen species (ROS) and calcium. We have shown that ANG-II type 1 receptor (AT1R) and prostaglandin E2 (PGE2) type 1 receptors (EP1R) are required in the subfornical organ (SFO) for ROS-mediated hypertension induced by slow-pressor ANG-II infusion. However, the signaling pathway associated with this process remains unclear. We sought to determine mechanisms underlying the ANG II-induced ROS and calcium influx in mouse SFO cells. Ultrastructural studies showed that cyclooxygenase 1 (COX-1) codistributes with AT1R in the SFO, indicating spatial proximity. Functional studies using SFO cells revealed that ANG II potentiated PGE2 release, an effect dependent on AT1R, phospholipase A2 (PLA2) and COX-1. Furthermore, both ANG II and PGE2 increased ROS formation. While the increase in ROS initiated by ANG II, but not PGE2, required the activation of the AT1R/PLA2/COX-1 pathway, both ANG II and PGE2 were dependent on EP1R and Nox2 as downstream effectors. Finally, ANG II potentiated voltage-gated L-type Ca2+ currents in SFO neurons via the same signaling pathway required for PGE2 production. Blockade of EP1R and Nox2-derived ROS inhibited ANG II and PGE2-mediated Ca2+ currents. We propose a mechanism whereby ANG II increases COX-1-derived PGE2 through the AT1R/PLA2 pathway, which promotes ROS production by EP1R/Nox2 signaling in the SFO. ANG II-induced ROS are coupled with Ca2+ influx in SFO neurons, which may influence SFO-mediated sympathoexcitation. Our findings provide the first evidence of a spatial and functional framework that underlies ANG-II signaling in the SFO and reveal novel targets for antihypertensive therapies.

scholarly journals Endothelin-1-Induced Microvascular ROS and Contractility in Angiotensin-II-Infused Mice Depend on COX and TP Receptors

Antioxidants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 193 ◽  
Author(s):  
Christopher S. Wilcox ◽  
Cheng Wang ◽  
Dan Wang
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Ros Generation ◽  
Oxygen Species ◽  
Ang Ii ◽  
Wild Type ◽  
Endothelin 1 ◽  
Ros Metabolism ◽  
Tp Receptors

(1) Background: Angiotensin II (Ang II) and endothelin 1 (ET-1) generate reactive oxygen species (ROS) that can activate cyclooxygenase (COX). However, thromboxane prostanoid receptors (TPRs) are required to increase systemic markers of ROS during Ang II infusion in mice. We hypothesized that COX and TPRs are upstream requirements for the generation of vascular ROS by ET-1. (2) Methods: ET-1-induced vascular contractions and ROS were assessed in mesenteric arterioles from wild type (+/+) and knockout (−/−) of COX1 or TPR mice infused with Ang II (400 ng/kg/min × 14 days) or a vehicle. (3) Results: Ang II infusion appeared to increase microvascular protein expression of endothelin type A receptors (ETARs), TPRs, and COX1 and 2 in COX1 and TPR +/+ mice but not in −/− mice. Ang II infusion increased ET-1-induced vascular contractions and ROS, which were prevented by a blockade of COX1 and 2 in TPR +/+ mice. ET-1 increased the activity of aortic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and decreased superoxide dismutase (SOD) 1, 2, and 3 in Ang-II-infused mice, which were prevented by a blockade of TPRs. (4) Conclusion: Activation of vascular TPRs by COX products are required for ET-1 to increase vascular contractions and ROS generation from NADPH oxidase and reduce ROS metabolism by SOD. These effects require an increase in these systems by prior infusion of Ang II.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

scholarly journals Up-regulation of glomerular COX-2 by angiotensin II: Role of reactive oxygen species

2005 ◽  
Vol 68 (5) ◽  
pp. 2143-2153 ◽  
Author(s):  
Edgar A. Jaimes ◽  
Run-Xia Tian ◽  
Damien Pearse ◽  
Leopoldo Raij
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cox 2

scholarly journals Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer’s Disease

2018 ◽  
Author(s):  
Yu-Te Lin ◽  
Yi-Chung Wu ◽  
Gwo-Ching Sun ◽  
Chiu-Yi Ho ◽  
Tzyy-Yue Wong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cognitive Impairment ◽  
Angiotensin Ii ◽  
Nucleus Tractus Solitarius ◽  
Glycogen Synthase ◽  
Reactive Oxygen ◽  
Hippocampal Damage ◽  
Oxygen Species ◽  
Ang Ii

Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer&rsquo;s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. In the present study, we aimed to determine whether treatment with resveratrol reduces reactive oxygen species (ROS) generation in the brain, thereby reducing cognitive impairment in rats with angiotensin II (Ang-II)-induced early AD. Male WKY rats with Ang-II-induced AD were treated with losartan or resveratrol for 2 weeks. Our results revealed that treatment with resveratrol (10 mg/kg/day) decreased blood pressure, increased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased ROS production in the nucleus tractus solitarius (NTS) in the Ang-II groups. In addition, inhibition of TauT231 phosphorylation in the hippocampus using resveratrol significantly abolished Ang-II-induced expression of Ab precursors, active caspase 3, and glycogen synthase kinase 3b (GSK-3b)Y216 while increasing AktS473 phosphorylation. Notably, resveratrol reversed impairments in hippocampal-dependent contextual memory induced by deleting NADPH oxidase and NOX2. Overall, our results suggest that resveratrol exerts neuroprotective effects against memory impairment and hippocampal damage in a rat model of early stage AD by reducing oxidative stress. These novel findings indicate that resveratrol may represent a pharmacological option for patients with hypertension at a risk of AD during old age.

scholarly journals Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer’s Disease †

2018 ◽  
Vol 7 (10) ◽  
pp. 329 ◽  
Author(s):  
Yu-Te Lin ◽  
Yi-Chung Wu ◽  
Gwo-Ching Sun ◽  
Chiu-Yi Ho ◽  
Tzyy-Yue Wong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Angiotensin Ii ◽  
Reactive Oxygen ◽  
Hippocampal Damage ◽  
Oxygen Species ◽  
Ang Ii

Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. Here, we aimed to determine whether reactive oxygen species (ROS) reduction by resveratrol in the brain leads to cognitive impairment reduction in rats with angiotensin II (Ang-II)-induced early AD. Male Wistar Kyoto (WKY) rats with Ang-II-induced AD were treated with losartan or resveratrol for two weeks. Our results show decreased blood pressure, increased hippocampal brain-derived neurotrophic factor (BDNF) level, and decreased nucleus tractus solitarius (NTS) ROS production in the Ang-II groups with losartan (10 mg/kg), or resveratrol (10 mg/kg/day) treatment. Furthermore, losartan inhibition of hippocampal TauT231 phosphorylation activated AktS473 phosphorylation, and significantly abolished Ang-II-induced Aβ precursors, active caspase 3, and glycogen synthase kinase 3β (GSK-3β)Y216 expressions. Consistently, resveratrol showed similar effects compared to losartan. Both losartan and resveratrol restored hippocampal-dependent contextual memory by NADPH oxidase 2 (NOX2) deletion and superoxide dismutase 2 (SOD2) elevation. Our results suggest that both losartan and resveratrol exert neuroprotective effects against memory impairment and hippocampal damage by oxidative stress reduction in early stage AD rat model. These novel findings indicate that resveratrol may represent a pharmacological option similar to losartan for patients with hypertension at risk of AD during old age.

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