ArticleCirculation2015
Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs.
Registry-linked trialOpen access · bronzeAbstract read
In one paragraph
Article in Circulation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04765644 (Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment), which is not on this map. Cited by 37 papers.
0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
9.2field-weighted citation impact, top 2% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)
Who cites it
37 citing papers in PubMed, 82 citations in OpenAlex.
- Substrain-Dependent Differences in Doxorubicin-Induced Cardiotoxicity in Adult C57BL/6 Mice.Cardiovascular toxicology · 2025Article
- Vascular and inflammatory biomarkers of cardiovascular events in non-steroidal anti-inflammatory drug users.European heart journal open · 2024Article
- Article
- Urinary Prostaglandin E2 Excretion and the Risk of Cardiovascular and Kidney Disease.Journal of the American Heart Association · 2024Article
- Biooriented Synthesis of Ibuprofen-Clubbed NovelACS omega · 2023Article
- The Emerging Therapeutic Role of Prostaglandin E2 Signaling in Pulmonary Hypertension.Metabolites · 2023Review
- Phytochemical mediated modulation of COX-3 and NFκB for the management and treatment of arthritis.Scientific reports · 2023Article
- Renal Function Underpins the Cyclooxygenase-2: Asymmetric Dimethylarginine Axis in Mouse and Man.Kidney international reports · 2023Article
- Levels of plasma Quaking and cyclooxygenase-2 predict in-stent restenosis in patients with coronary artery disease after percutaneous coronary intervention.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2022Article
- Cytokine-Induced JAK2-STAT3 Activates Tissue Regeneration under Systemic or Local Inflammation.International journal of molecular sciences · 2022Article
- Studies on metal-organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension.Scientific reports · 2021Article
- Dissect the immunity using cytokine profiling and NF-kB target gene analysis in systemic inflammatory minipig model.PloS one · 2021Article
- Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.Cardiovascular research · 2020Article
- Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Eicosanoids: Atherosclerosis and cardiometabolic health.Journal of clinical & translational endocrinology · 2020Review
- Impact of drugs on venous thromboembolism risk in surgical patients.European journal of clinical pharmacology · 2019Review
- Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system.British journal of pharmacology · 2019Review
- The COX-2/prostanoid signaling cascades in seizure disorders.Expert opinion on therapeutic targets · 2019Review
- EP3 Blockade Adds to the Effect of TP Deficiency in Alleviating Endothelial Dysfunction in Atherosclerotic Mouse Aortas.Frontiers in physiology · 2019Article
- Radiosynthesis and Preclinical Evaluation ofContrast media & molecular imaging · 2019Article
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Authors and funding
14 authors at 4 institutions in 2 countries.
Blerina Ahmetaj-ShalaFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Nicholas S KirkbyFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Rebecca KnowlesFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Malak Al'YamaniFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Sarah MaziFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Zhen WangFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Arthur T TuckerFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Louise MackenzieFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Paul C J ArmstrongFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Rolf M NüsingFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
James A P TomlinsonFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Timothy D WarnerFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
James LeiperFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
Jane A MitchellFrom the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.). j.a.mitchell@ic.ac.uk.
Hammersmith Hospital · GBKing Saud University · SAImperial College London · GBUniversity of Hertfordshire · GB
Funding
British Heart Foundation FS/12/53/29643Medical Research Council MC_U120097118Wellcome Trust 0852551Z108/Z
Abstract
backgroundCardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified. METHODS AND
resultsTranscriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.
conclusionsWe identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.
Indexed as
AdultAnimalsAnti-Inflammatory AgentsArginineBiomarkersCardiovascular DiseasesCyclooxygenase 2Cyclooxygenase 2 InhibitorsFemaleHumansMaleMiceMice, Inbred C57BLMice, KnockoutOrgan Culture TechniquesYoung AdultAnti-Inflammatory AgentsArginineBiomarkersCyclooxygenase 2Cyclooxygenase 2 InhibitorsN,N-dimethylargininePtgs2 protein, mouseendotheliumkidneynitric oxidepharmacologyprostaglandins
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Registered trials
NCT04765644ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.