Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory

2004 ◽  
Vol 286 (5) ◽  
pp. F945-F954 ◽  
Author(s):  
Anderson Ricardo Roman Gonçalves ◽  
Clarice Kazue Fujihara ◽  
Ana Lúcia Mattar ◽  
Denise Maria Avancini Costa Malheiros ◽  
I. L. Noronha ◽  
...  
Keyword(s):  
Renal Injury ◽  
Sham Operation ◽  
Ang Ii ◽  
Treatment Groups ◽  
Renal Structure ◽  
Renal Ablation ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Antiinflammatory Effects ◽  
Structural Injury

Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with ⅚ renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT1 receptor (AT1R); 2) the renoprotective and antiinflammatory effects of an association between the AT1R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nxpre). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: NxV (vehicle), NxLos (Los), NxNOF (NOF), and NxLos/NOF (Los/NOF). Nxpre rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT1R distribution shifted from mostly tubular in S to predominantly interstitial in Nxpre. All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT1R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT1R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.

Chronic inhibition of nuclear factor-κB attenuates renal injury in the 5/6 renal ablation model

2007 ◽  
Vol 292 (1) ◽  
pp. F92-F99 ◽  
Author(s):  
Clarice K. Fujihara ◽  
Gláucia R. Antunes ◽  
Ana L. Mattar ◽  
Denise M. A. C. Malheiros ◽  
José M. Vieira ◽  
...  
Keyword(s):  
Renal Injury ◽  
Immunohistochemical Analysis ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Sham Operation ◽  
Ang Ii ◽  
Renal Ablation ◽  
Glomerular Hypertension ◽  
New Strategy ◽  
Ablation Model

Recent studies indicated that the nuclear transcription factor, NF-κB, activates a number of proinflammatory genes in subjects with progressive nephropathies. We investigated whether NF-κB inhibition limits progressive renal injury in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats were subdivided in four groups: S ( n = 16), subjected to sham operation; S+PDTC ( n = 18), sham-operated rats receiving the NF-κB inhibitor pyrrolidine-dithiocarbamate (PDTC; 60 mg·kg−1·day−1) in drinking water; Nx ( n = 16), Nx rats receiving vehicle only; and Nx+PDTC ( n = 19), Nx rats given PDTC as above. Thirty days after renal ablation, Nx rats exhibited systemic and glomerular hypertension. Only the former was attenuated by PDTC treatment. Sixty days after renal ablation, Nx rats exhibited marked hypertension, albuminuria and creatinine retention, as well as glomerulosclerosis and cortical interstitial expansion/inflammation. Immunohistochemical analysis of Nx rats showed renal interstitial infiltration by macrophages and by cells staining positively for ANG II and its receptor, AT1. Glomerular and interstitial cells expressing the p65 subunit of the NF-κB system were also found. PDTC treatment attenuated renal injury and inflammation, as well as the density of cells staining positively for the p65 subunit. Activation of the NF-κB system plays an important role in the pathogenesis of renal injury in the Nx model. Inhibition of this system may represent a new strategy to prevent the progression of chronic kidney disease.

Sex-dependent hypertension and renal changes in aged rats with altered renal development

2014 ◽  
Vol 307 (4) ◽  
pp. F461-F470 ◽  
Author(s):  
Fara Saez ◽  
Virginia Reverte ◽  
Alexander Paliege ◽  
Juan Manuel Moreno ◽  
María T. Llinás ◽  
...  
Keyword(s):  
Old Age ◽  
Renal Damage ◽  
Macula Densa ◽  
Male Rats ◽  
Renal Development ◽  
Ang Ii ◽  
Electron Microscopic ◽  
Renal Structure ◽  
Renal Changes ◽  
Cox 2

Numerous studies have evaluated blood pressure (BP) and renal changes in several models of developmental programming of hypertension. The present study examined to what extent BP, renal hemodynamic, and renal structure are affected at an old age in male and female animals with altered renal development. It also evaluated whether renal damage is associated with changes in cyclooxygenase (COX)-2 and neuronal nitric oxide synthase (NOS1) expression and immunoreactivity. Experiments were carried out in rats at 10–11 and 16–17 mo of age treated with vehicle or an ANG II type 1 receptor antagonist during the nephrogenic period (ARAnp). A progressive increment in BP and a deterioration of renal hemodynamics were found in both sexes of ARAnp-treated rats, with these changes being greater ( P < 0.05) in male rats. The decrease in glomerular filtration rate at the oldest age was greater ( P < 0.05) in male (74%) than female (32%) ARAnp-treated rats. Sex-dependent deterioration of renal structure was demonstrated in optical and electron microscopic experiments. COX-2 and NOS1 immunoreactivity were enhanced in the macula densa of male but not female ARAnp-treated rats. The present study reports novel findings suggesting that stimuli that induce a decrease of ANG II effects during renal development lead to a progressive increment in BP and renal damage at an old age in both sexes, but these BP and renal changes are greater in males than in females. The renal damage is associated with an increase of COX-2 and NOS1 in the macula densa of males but not females with altered renal development.

scholarly journals Peroxisome Proliferator Activated Receptor-αAgonist Slows the Progression of Hypertension, Attenuates Plasma Interleukin-6 Levels and Renal Inflammatory Markers in Angiotensin II Infused Mice

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Justin L. Wilson ◽  
Rong Duan ◽  
Ahmed El-Marakby ◽  
Abdulmohsin Alhashim ◽  
Dexter L. Lee
Keyword(s):  
Angiotensin Ii ◽  
Inflammatory Markers ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Induced Hypertension ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Renal Expression

The anti-inflammatory properties of PPAR-αplays an important role in attenuating hypertension. The current study determines the anti-hypertensive and anti-inflammatory role of PPAR-αagonist during a slow-pressor dose of Ang II (400 ng/kg/min). Ten to twelve week old male PPAR-αKO mice and their WT controls were implanted with telemetry devices and infused with Ang II for 12 days. On day 12 of Ang II infusion, MAP was elevated in PPAR-αKO mice compared to WT (161±4 mmHg versus145±4 mmHg) and fenofibrate (145 mg/kg/day) reduced MAP in WT + Ang II mice (134±7 mmHg). Plasma IL-6 levels were higher in PPAR-αKO mice on day 12 of Ang II infusion (30±4versus8±2 pg/mL) and fenofibrate reduced plasma IL-6 in Ang II-treated WT mice (10±3 pg/mL). Fenofibrate increased renal expression of CYP4A, restored renal CYP2J expression, reduced the elevation in renal ICAM-1, MCP-1 and COX-2 in WT + Ang II mice. Our results demonstrate that activation of PPAR-αattenuates Ang II-induced hypertension through up-regulation of CYP4A and CYP2J and an attenuation of inflammatory markers such as plasma IL-6, renal MCP-1, renal expression of ICAM-1 and COX-2.

Pioglitazone reduces angiotensin II-induced COX-2 expression through inhibition of ROS production and ET-1 transcription in vascular cells from spontaneously hypertensive rats

2014 ◽  
Vol 306 (11) ◽  
pp. H1582-H1593 ◽  
Author(s):  
Jose V. Pérez-Girón ◽  
Roberto Palacios ◽  
Angela Martín ◽  
Raquel Hernanz ◽  
Andrea Aguado ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Mrna Levels ◽  
Ros Production ◽  
Activator Protein 1 ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Cox 2 ◽  
Anti Inflammatory

Glitazones have anti-inflammatory properties by interfering with the transcription of proinflammatory genes, such as cyclooxygenase (COX)-2, and with ROS production, which are increased in hypertension. This study analyzed whether pioglitazone modulates COX-2 expression in hypertension by interfering with ROS and endothelin (ET)-1. In vivo, pioglitazone (2.5 mg·kg−1·day−1, 28 days) reduced the greater levels of COX-2, pre-pro-ET-1, and NADPH oxidase (NOX) expression and activity as well as O2·− production found in aortas from spontaneously hypertensive rats (SHRs). ANG II increased COX-2 and pre-pro-ET-1 levels more in cultured vascular smooth muscle cells from hypertensive rats compared with normotensive rats. The ETA receptor antagonist BQ-123 reduced ANG II-induced COX-2 expression in SHR cells. ANG II also increased NOX-1 expression, NOX activity, and superoxide production in SHR cells; the selective NOX-1 inhibitor ML-171 and catalase reduced ANG II-induced COX-2 and ET-1 transcription. ANG II also increased c-Jun transcription and phospho-JNK1/2, phospho-c-Jun, and p65 NF-κB subunit nuclear protein expression. SP-600125 and lactacystin, JNK and NF-κB inhibitors, respectively, reduced ANG II-induced ET-1, COX-2, and NOX-1 levels and NOX activity. Pioglitazone reduced the effects of ANG II on NOX activity, NOX-1, pre-pro-ET-1, COX-2, and c-Jun mRNA levels, JNK activation, and nuclear phospho-c-Jun and p65 expression. In conclusion, ROS production and ET-1 are involved in ANG II-induced COX-2 expression in SHRs, explaining the greater COX-2 expression observed in this strain. Furthermore, pioglitazone inhibits ANG II-induced COX-2 expression likely by interfering with NF-κB and activator protein-1 proinflammatory pathways and downregulating ROS production and ET-1 transcription, thus contributing to the anti-inflammatory properties of glitazones.

scholarly journals COX-2-derived prostaglandins as mediators of the deleterious effects of nicotine in chronic kidney disease

2020 ◽  
Vol 318 (2) ◽  
pp. F475-F485 ◽  
Author(s):  
S. Rangarajan ◽  
G. Rezonzew ◽  
P. Chumley ◽  
H. Fatima ◽  
M. Y. Golovko ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Tap Water ◽  
Osmotic Minipump ◽  
Renal Ablation ◽  
Cox 2

Tobacco smoking has been identified as a risk factor in the progression of chronic kidney disease (CKD). In previous studies, we showed that nicotine induces cyclooxygenase (COX)-2 expression in vivo and in vitro and that the administration of nicotine in vivo worsens the severity of renal injury in a model of subtotal renal ablation. In the present study, we tested the role of COX-2-derived prostaglandins on the deleterious effects of nicotine in CKD. Sham and 5/6 nephrectomy (5/6Nx) rats received tap water or nicotine (100 μg/mL) in the drinking water for 12 wk. Additional groups also systemically received the COX-2 inhibitor NS-398 (1.5 mg·kg−1·day−1 via osmotic minipump). The administration of nicotine worsened renal injury and proteinuria in 5/6Nx rats and increased proteinuria in sham rats. 5/6Nx rats had increased cortical production of the prostaglandins PGE2, PGI2, PGD2, and PGF2α and of thromboxane A2. In these rats, nicotine reduced the production of all prostaglandins examined except thromboxane A2. Treatment with the COX-2 inhibitor NS-398 resulted in complete inhibition of all prostaglandins studied and ameliorated renal injury and proteinuria in 5/6Nx rats on nicotine but not in 5/6 Nx rats on tap water. Nicotine also reduced the expression of megalin in all groups examined, and this was partially prevented by COX-2 inhibition. In the present study, we showed that in CKD, nicotine worsens renal injury at least in part by producing an imbalance in the production of prostaglandins. This imbalance in the production of prostaglandins likely plays a role in the deleterious effects of smoking on the progression of CKD.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals Processed Scutellaria baicalensis Georgi Extract Alleviates LPS-Induced Inflammatory and Oxidative Stress through a Crosstalk between NF-κB and KEAP1/NRF2 Signaling in Macrophage Cells

2021 ◽  
Vol 11 (13) ◽  
pp. 6055
Author(s):  
Akhtar Ali ◽  
En-Hyung Kim ◽  
Jong-Hyun Lee ◽  
Kang-Hyun Leem ◽  
Shin Seong ◽  
...  
Keyword(s):  
Scutellaria Baicalensis ◽  
Raw 264.7 Cells ◽  
Prostaglandin E ◽  
Scutellaria Baicalensis Georgi ◽  
Anticancer Effects ◽  
Tnf Α ◽  
Clinical Benefits ◽  
Anti Oxidant ◽  
Cox 2 ◽  
Anti Inflammatory

Prolonged inflammation results in chronic diseases that can be associated with a range of factors. Medicinal plants and herbs provide synergistic benefits based on the interaction of multiple phytochemicals. The dried root of Scutellaria baicalensis Georgi and its compounds possess anti-inflammatory, anti-oxidative, and anticancer effects. Processing is a traditional method to achieve clinical benefits by improving therapeutic efficacy and lowering toxicity. In this study, we investigated the anti-inflammatory and anti-oxidant effect of processed Scutellaria baicalensis Georgi extract (PSGE) against lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Data using Griess assay and ELISA showed that PSGE decreased nitric oxide and prostaglandin E2 (PGE2) levels against LPS. PSGE treatment up-regulated 15-hydroxyprostaglandin dehydrogenase (PGDH), while cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 expression did not change. Interestingly, PGE2 inhibition was regulated by prostaglandin catabolic enzyme 15-PGDH rather than COX-2/mPGES-1, enzymes essential for PGE2 synthesis. Additionally, PSGE-suppressed LPS-induced IL-6 and TNF-α production through NF-κB signaling. NF-κB release from an inactive complex was inhibited by HO-1 which blocked IκBα phosphorylation. The ROS levels lowered by PSGE were measured with the H2DCFDA probe. PSGE activated NRF2 signaling and increased antioxidant Hmox1, Nqo1, and Txn1 gene expression, while reducing KEAP1 expression. In addition, pharmacological inhibition of HO-1 confirmed that the antioxidant enzyme induction by PSGE was responsible for ROS reduction. In conclusion, PSGE demonstrated anti-inflammatory and anti-oxidant effects due to NRF2/HO-1-mediated NF-κB and ROS inhibition.

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

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