The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine formation, and stimulates apoptosis in mucosa during early colonic inflammation in rats

Tardieu, Didier; Jaeg, Jean-Philippe; Deloly, Alain; Corpet, Denis E.; Cadet, Jean; Petit, Claude

doi:10.1093/carcin/21.5.973

Cited by 79 publications

(48 citation statements)

References 35 publications

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“…The antioxidative effect of nimesulide was reported previously in human neutrophils 17 and in rat colonic mucosa. 18 Here, our result showed that nimesulide is also an antioxidative agent in cardiovascular tissues.…”

Section: Discussionmentioning

confidence: 54%

Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II–Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats

Laplante

Champlain

2005

Hypertension

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Abstract-Angiotensin II is an important oxidative stress mediator. Our previous studies have indicated that the potent antioxidative properties of acetylsalicylic acid play an important role in its cardiovascular protective effects. There are some ongoing controversies concerning the use of selective cyclooxygenase-2 inhibitors in cardiovascular disease. The aim of this study was to determine whether the cyclooxygenase-2 selective inhibitors rofecoxib and nimesulide possess antioxidative and cardiovascular protective effects against angiotensin II. Chronic subcutaneous angiotensin II infusion increased cardiovascular but not colonic tissue superoxide production, heart/body weight ratio, and blood pressure. Moreover, angiotensin II selectively increased cardiac cyclooxygenase-2 but not cyclooxygenase-1 expression, which was totally prevented by acetylsalicylic acid treatment. Similar to acetylsalicylic acid, rofecoxib or nimesulide treatments significantly attenuated angiotensin II-induced oxidative stress, hypertension, and cardiac NAD(P)H oxidase subunit p47 phox expression. Rofecoxib also reduced cardiac hypertrophy. Treatment with nonselective anti-inflammatory drugs ibuprofen, indomethacin, or salicylic acid did not show any effect on angiotensin II-induced superoxide production, hypertension, or cardiac hypertrophy. Although acetylsalicylic acid and salicylic acid inhibited angiotensin II-induced nuclear factor B (NF-B) activation, nimesulide did not modify NF-B activation. In conclusion, cyclooxygenase-2 pathway is implicated in angiotensin II-induced oxidative stress and deleterious cardiovascular changes. Rofecoxib and nimesulide produced significant antioxidative effect by reducing NAD(P)H oxidase-dependent superoxide generation. These effects seem to be independent of NF-B inhibition.

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Section: Discussionmentioning

confidence: 54%

Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II–Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats

Laplante

Champlain

2005

Hypertension

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“…In addition to producing biologically active prostanoids, COX-2 generates reactive oxygen species and oxidative metabolites such as malondialdehyde, 71 which have been shown to contribute to DNA oxidation damage and cell apoptosis. 72 The molecular processes that the proliferating cell develops to protect its DNA and cell function are largely unknown. The COX-2 transcriptional control serves as an excellent model for unraveling the molecular mechanisms, and the results should have a great impact on understanding fundamental cytoprotection program and developing transcription-targeted therapeutic strategies.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Control of COX-2 via C/EBPβ

Wu¹,

Liou²,

Cieslik³

2005

ATVB

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Abstract-Cyclooxygenase-2 (COX-2) is a highly inducible enzyme exerting diverse actions on cell functions, including proliferation, migration, and DNA damage. Enhanced COX-2 expression may be protective, but excessive expression may be harmful, causing inflammation, atheromatous plaque instability, and intimal hyperplasia. COX-2 transcriptional activation by proinflammatory mediators has been extensively characterized. In this review, the role of C/EBP in regulating COX-2 transcription is highlighted. Recent advances in control of COX-2 transcription by aspirin and salicylate and by a cell cycle-dependent endogenous mechanism are described. The recent progress sheds light on the pathophysiological mechanisms of COX-2 and new transcription-based strategy for controlling COX-2 overexpression and COX-2-mediated cardiovascular diseases. Key Words: aspirin Ⅲ C/EBP Ⅲ COX-2 Ⅲ inflammation Ⅲ NF-B C yclooxygenase (COX, also known as prostaglandin [PG] H synthase or PGHS) occupies a pivotal position in PG and thromboxane A 2 (TXA 2 ) synthesis. It is a bifunctional enzyme containing a cyclooxygenase catalytic center, which adds 2 oxygen (bisoxygenation) to arachidonic acid (AA) to form a peroxide, PGG 2 , and a peroxidase active site, which reduces PGG 2 to PGH 2 . 1 PGH 2 is a common precursor for synthesis of biologically active prostanoids, including PGE 2 , PGI 2 (prostacyclin), TXA 2 , PGD 2 , and PGF 2␣ . There are 2 isoforms of COX; COX-1 is constitutively expressed, whereas COX-2 is inducible by diverse cytokines, mitogenic factors, and endotoxins. 2 These 2 isoforms of COX share a high degree of sequence identity and structural resemblance. 1 Both are homodimers with a long substrate channel and a stretch of hydrophobic residues that anchor the enzymes to the inner surface of endoplasmic reticulum and nuclear envelope. 3 Both enzymes contain heme with almost identical spectral characteristics and comparable catalytic parameters. 1 Thus, these 2 enzymes catalyze the generation of a similar profile of AA metabolites and might seem to have overlapped cellular activities. However, results from recent studies have provided unequivocal evidence for distinct cellular activities and different pathophysiological roles between these 2 enzymes. COX-2 has been implicated in diverse physiological and pathophysiological processes from renal and cardiovascular physiology to inflammation and tumorigenesis. 4 -9 In this review, we concentrate on its roles in cardiovascular diseases, with a focus on novel aspects of its transcriptional activation by proinflammatory mediators and the control of its transcriptional activation by aspirin and an endogenous mechanism. COX-2 Overexpression and Cardiovascular DiseasesUnder physiological conditions, COX-2 expression in vascular and cardiac endothelial cells is stimulated primarily by physical forces such as shear stress. 10,11 On endothelial activation, cytosolic phospholipase A 2 is translocated and colocalized with COX-2 and prostacyclin (PGI 2 ) synthase to endoplasmic reticulum and...

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“…In addition to CYP1, several sources of ROS exist, notably the mitochondrial electron transport chain, nicotinamide adenine dinucleotide phosphate-oxidase, and cyclooxygenases. [39][40][41] Note that IAA also has a prooxidant effect in renal tubular cells. 42 Via prooxidant, proinflammatory, and prothrombotic 9 mechanisms, IAA could act as a mediator of endotheliotoxicity of uremia.…”

Section: Discussionmentioning

confidence: 99%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

Journal of the American Society of Nephrology

257

225

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In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA.3.73 mM) than in the lower IAA group (IAA,3.73 mM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kB pathway.

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The COX-2 inhibitor nimesulide suppresses superoxide and 8-hydroxy-deoxyguanosine formation, and stimulates apoptosis in mucosa during early colonic inflammation in rats

Cited by 79 publications

References 35 publications

Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II–Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats

Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II–Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats

Transcriptional Control of COX-2 via C/EBPβ

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

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