Cited by 1,957Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionEicosanoids and Hypertension Pharmacology

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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

Förstermann, Ulrich, Münzel, Thomas·2006·Circulation

DOI 10.1161/circulationaha.105.602532

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Abstract

Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate l -arginine to l -citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate l -arginine, and the essential cofactor (6 R )-5,6,7,8-tetrahydro- l -biopterin (BH 4 ), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O 2 · − ) reacts avidly with vascular NO· to form peroxynitrite (ONOO − ). The cofactor BH 4 is highly sensitive to oxidation by ONOO − . Diminished levels of BH 4 promote O 2 · − production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH 4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH 4 levels as well.

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Griendling, K. K., Sorescu, D., & Ushio-Fukai, M. (2000) · Circulation Research · doi:10.1161/01.res.86.5.494 · Cited by 2,886
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.
Rajagopalan, S., Kurz, S. D., Münzel, T. F., Tarpey, M. M., Freeman, B. Α., Griendling, K. K., & Harrison, D. G. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118623 · Cited by 2,466
Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease
Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T., & Münzel, T. (2001) · Circulation · doi:10.1161/hc4601.099485 · Cited by 1,961
Hypercholesterolemia increases endothelial superoxide anion production.
Ohara, Y., Peterson, T. E., & Harrison, D. G. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116491 · Cited by 1,765
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
Landmesser, U., Dikalov, S., Price, S. R., McCann, L., Fukai, T., Holland, S. M., Mitch, W. E., & Harrison, D. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200314172 · Cited by 1,660
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
Landmesser, U., Dikalov, S., Price, S. R., McCann, L. A., Fukai, T., Holland, S. M., Mitch, W. E., & Harrison, D. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci14172 · Cited by 1,652
Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus
Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., Skatchkov, M. P., Thaiss, F., Stahl, R. A. K., Warnholtz, A., et al. (2001) · Circulation Research · doi:10.1161/01.res.88.2.e14 · Cited by 1,190
Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
Förstermann, U., Closs, E. I., Pollock, J. S., Nakane, M., Schwarz, P., Gath, I., & Kleinert, H. (1994) · Hypertension · doi:10.1161/01.hyp.23.6.1121 · Cited by 1,110
Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells.
Pollock, J. S., Förstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M., & Murad, F. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.23.10480 · Cited by 979
Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.
Ting, H. H., Timimi, F. K., Boles, K., Creager, S. J., Ganz, P., & Creager, M. A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118394 · Cited by 869

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10.1161/res.86.3.347 · DOI
Li H Witte K August M Brausch I Gödtel-Armbrust U Habermeier A Closs EI Oelze M Münzel T Förstermann U. Reversal of eNOS uncoupling and upregulation of eNOS expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol. In press.
10.1161/res.88.2.e14 · DOI
10.1161/circ.99.15.2027 · DOI
10.1161/res.86.5.494 · DOI
10.1161/circ.94.11.2756 · DOI
10.1161/circ.101.11.1261 · DOI
10.1161/circ.100.21.2131 · DOI
10.1161/hyp.30.1.57 · DOI
10.1161/res.77.3.510 · DOI
10.1161/circ.103.9.1282 · DOI
10.1161/hyp.33.6.1353 · DOI
10.1161/res.86.1.e7 · DOI
10.1161/res.86.2.e36 · DOI
10.1161/circ.104.10.1119 · DOI
10.1161/res.87.2.99 · DOI
10.1161/res.87.7.566 · DOI
10.1161/hyp.38.5.1044 · DOI
10.1161/circ.104.22.2673 · DOI
10.1161/circ.94.1.6 · DOI
10.1161/circ.97.3.237 · DOI
10.1161/atvb.22.1.6 · DOI
10.1161/atvb.20.1.185 · DOI

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“tetrahydrobiopterin [9].”
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Background
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“However, after heart failure, the bioavailability of eNOS-derived NO is severely reduced [38, 39].”
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Background
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Background
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Background
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BackgroundInfluential
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“[44] Forstermann U, Munzel T.”
Background
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Background
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Noguchi, K., Hamadate, N., Matsuzaki, T., Sakanashi, M., Nakasone, J., Uchida, T., Arakaki, K., Kubota, H., Ishiuchi, S., Masuzaki, H., et al. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01089.2010 · Cited by 38
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“L-arginine found to have beneficial effect in hypercholesterolemia in animals as well as humans [68].”
Transcriptional and Posttranslational Regulation of eNOS in the Endothelium
Fulton, D. J. (2016) · Advances in pharmacology · doi:10.1016/bs.apha.2016.04.001 · Cited by 37
New Insights in the Pathophysiology of Antiphospholipid Syndrome
Sacharidou, A., Shaul, P. W., & Mineo, C. (2017) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0036-1597286 · Cited by 38
Oxidative and nitrosative stress during pulmonary ischemia-reperfusion injury: from the lab to the OR
Gielis, J. F., Beckers, P. A. J., Briedé, J. J., Cos, P., & Schil, P. E. V. (2017) · Annals of Translational Medicine · doi:10.21037/atm.2017.03.32 · Cited by 38
Evaluation of Endothelial Function by Flow-Mediated Dilation: a Comprehensive Review in Rheumatic Disease
Moroni, L., Selmi, C. F., Angelini, C., & Meroni, P. L. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-017-0465-7 · Cited by 37
The potential of transdermal nitric oxide treatment for diabetic peripheral neuropathy and diabetic foot ulcers
Walton, D. M., Minton, S. D., & Cook, A. D. (2018) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2018.07.003 · Cited by 39
A Detailed Insight of the Anti-inflammatory Effects of Curcumin with the Assessment of Parameters, Sources of ROS and Associated Mechanisms
Wal, P., Saraswat, N., Pal, R. S., Wal, A., & Chaubey, M. (2019) · Open Medicine Journal · doi:10.2174/1874220301906010064 · Cited by 38
Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury
Zhai, R., Xu, H., Hu, F., Wu, J., Kong, X., & Sun, X. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15059 · Cited by 38
“In several diseases such as diabetes and hypertension, the uncoupling of eNOS characterizes the endothelial dysfunction, as it decreases production of NO and increases the generation of superoxide (Forstermann & Munzel, 2006).”
Background
Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and β-Arrestins as Targets
Kayki‐Mutlu, G., & Koch, W. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020521 · Cited by 39
“Conversely, increased eNOS is also reported to be associated with a cardiovascular risk due to excess ROS production [30].”
Background
Correlation of nitric oxide produced by an inducible nitric oxide synthase-like protein with enhanced expression of the phenylpropanoid pathway in Inonotus obliquus cocultured with Phellinus morii
Zhao, Y., Xi, Q., Xu, Q., He, M., Ding, J., Dai, Y., Keller, N. P., & Zheng, W. (2015) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-014-6367-2 · Cited by 38
High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction
Mohan, S., Konopiński, R., Yan, B., Centonze, V. E., & Natarajan, M. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00575.2007 · Cited by 38
Growth Hormone Exerts Acute Vascular Effects Independent of Systemic or Muscle Insulin-like Growth Factor I
Li, G., del Rincon, J. P., Jahn, L. A., Wu, Y., Gaylinn, B. D., Thorner, M. O., & Liu, Z. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2021 · Cited by 39
Vascular Redox Signaling, Endothelial Nitric Oxide Synthase Uncoupling, and Endothelial Dysfunction in the Setting of Transportation Noise Exposure or Chronic Treatment with Organic Nitrates
Münzel, T. F., & Daiber, A. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0006 · Cited by 40
“…of inhibition of eNOS since uncoupling causes the enzyme to change from an NO to O2 - donor, thereby changing the biological environment from a vasodilator/antiatherosclerotic and thus beneficial to a harmful/proatherosclerotic phenotype (Forstermann and Munzel, 2006; Munzel et al, 2005b).”
BackgroundInfluential
Promising remedies for cardiovascular disease: Natural polyphenol ellagic acid and its metabolite urolithins
Li, J., Liao, R., Zhang, S., Weng, H., Liu, Y., Tao, T., Yu, F., Li, G., & Wu, J. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154867 · Cited by 37
Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives
Xie, P.-L., Zheng, M.-Y., Han, R., Chen, W., & Mao, J.-H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1366061 · Cited by 40
“Disruptions in the process are commonly associated with disease (Förstermann and Münzel, 2006).”
Background
Aged garlic extract restores nitric oxide bioavailability in cultured human endothelial cells even under conditions of homocysteine elevation
Weiss, N., Papatheodorou, L., Morihara, N., Hilge, R., & Ide, N. (2012) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2012.10.045 · Cited by 37
Role of Arginine Guanidinium Moiety in Nitric-oxide Synthase Mechanism of Oxygen Activation
Giroud, C., Moreau, M., Mattioli, T. A., Balland, V., Boucher, J., Li, Y., Stuehr, D. J., & Santolini, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.038240 · Cited by 37
Direct Renin Inhibition With Aliskiren Protects Against Myocardial Ischemia/Reperfusion Injury by Activating Nitric Oxide Synthase Signaling in Spontaneously Hypertensive Rats
Zhang, W., Han, Y., Meng, G., Bai, W., Xie, L., Lu, H., Shao, Y., Wei, L., Pan, S., Zhou, S., et al. (2014) · Journal of the American Heart Association · doi:10.1161/jaha.113.000606 · Cited by 37
“NO scavenges superoxide anion and protects against impairment of vascular endothelial function.(24,25) There is accumulating evidence that oxidative stress induces I/R injury, and reactive oxygen species and free radicals have long been recognized as major mediators of I/R injury.”
Background
Pretreatment with Astragaloside IV protects human umbilical vein endothelial cells from hydrogen peroxide induced oxidative stress and cell dysfunction via inhibiting eNOS uncoupling and NADPH oxidase – ROS – NF-κB pathway
Xu, C., Tang, F., Lü, M., Yang, J., Han, R., Mei, M., Hu, J., & Wang, H. (2016) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2015-0572 · Cited by 37
AMA0428, A Potent Rock Inhibitor, Attenuates Early and Late Experimental Diabetic Retinopathy
Hollanders, K., Hove, I. V., Sergeys, J., Bergen, T. V., Lefevere, E., Kindt, N., Castermans, K., Vandewalle, E., van Pelt, J. F., Moons, L., et al. (2016) · Current Eye Research · doi:10.1080/02713683.2016.1183030 · Cited by 38
Near-infrared spectroscopy assessment of microvasculature detects difference in lower limb vascular responsiveness in obese compared to lean individuals
Soares, R. N., & Murias, J. M. (2018) · Microvascular Research · doi:10.1016/j.mvr.2018.01.008 · Cited by 37
Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status
Lopez, M., Lax, A., Vicente, Á. H., Guillen, E. S., Hernández-Martínez, A. M., del Palacio, M. J. F., Bayés‐Genís, A., & Pascual-Figal, D. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-70454-8 · Cited by 37
Monoterpenes and their derivatives as agents for cardiovascular disease management: A systematic review and meta-analysis
Silva, E. A. P., dos Santos, D. M., de Carvalho, F. O., de Menezes, I. A. C., Barreto, A. S., Souza, D. S., Quintans‐Júnior, L. J., & dos Santos, M. R. V. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153451 · Cited by 37
A high-performance genetically encoded fluorescent biosensor for imaging physiological peroxynitrite
Chen, Z., Zhang, S., Li, X., & Ai, H. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.013 · Cited by 35
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Sahebnasagh, A., Saghafi, F., Negintaji, S., Hu, T., Shabani-Borujeni, M., Safdari, M., Ghaleno, H. R., Miao, L., Qi, Y., Wang, M., et al. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210707194543 · Cited by 39
Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications
Higashikuni, Y., Liu, W., Obana, T., & Sata, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222112081 · Cited by 38
“Nitric oxide also inhibits thromboinflammation and reactive oxygen species production by acting on endothelial cells [207].”
Background
Heme oxygenase-1 in cardiovascular diseases: molecular mechanisms and clinical perspectives.
Wang, C., & Chau, L. (2010) · PubMed · Cited by 36
Fat intake and cardiovascular response
Damjanovi, M., & Barton, M. (2008) · Current Hypertension Reports · doi:10.1007/s11906-008-0007-0 · Cited by 38
Redox state, oxidative stress and endothelial dysfunction in heart failure: the puzzle of nitrate–thiol interaction
Parodi, O., Maria, R. D., & Roubina, E. (2007) · Journal of Cardiovascular Medicine · doi:10.2459/jcm.0b013e32801194d4 · Cited by 37
Weibel–Palade bodies—sentinels of acute stress
Goligorsky, M. S., Patschan, D., & Kuo, M. (2009) · Nature Reviews Nephrology · doi:10.1038/nrneph.2009.87 · Cited by 37
“This preliminary finding, in conjunction with the well-established uncoupled state of endothelial nitric oxide synthase in dysfunctional endothelial cells”
Result
Nitric oxide and kidney oxygenation
Palm, F., Teerlink, T., & Hansell, P. (2008) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e32831c4cdf · Cited by 37
The effects of folic acid and nitric oxide synthase inhibition on coronary flow and oxidative stress markers in isolated rat heart
Djuric, D. M., Vušanović, A., & Jakovljevic, V. L. (2006) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-006-9381-6 · Cited by 38
“Furthermore, there is evidence that vitamin C may have direct effects on activity of NOS, possibly through an effect on tetrahydrobiopterin (Heller et al. 1999; Huang et al. 2000; Förstermann and Münzel 2006).”
Background
Increased Oxidant Activity Mediates Vascular Dysfunction in Vibration Injury
Hughes, J. M., Wirth, O., Krajnak, K., Miller, R., Flavahan, S., Berkowitz, D. E., Welcome, D. E., & Flavahan, N. A. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.144618 · Cited by 37
“NO is vasoprotective and acts to inhibit platelet aggregation and adhesion and vascular remodeling and inflammation, whereas H2O2 and other oxidants can initiate pathological changes in the vasculature, stimulating inflammatory genes, vascular remodeling, and enhanced vasoconstriction (Boulden et al., 2006; Försterman…”
Background
Inhibitor of G Protein-Coupled Receptor Kinase 2 Normalizes Vascular Endothelial Function in Type 2 Diabetic Mice by Improving β-Arrestin 2 Translocation and Ameliorating Akt/eNOS Signal Dysfunction
Taguchi, K., Matsumoto, T., Kamata, K., & Kobayashi, T. (2012) · Endocrinology · doi:10.1210/en.2012-1101 · Cited by 36
“eNOS and Akt play a major role in the regulation of vascular endothelial function (31, 35), and these are consistent with previous data demonstrating that Akt phosphorylation leads to eNOS phosphorylation and subsequent activation of eNOS enzymatic activity (13–16, 36, 37).”
Result
Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity
Toyama, K., Nakamura, T., Kataoka, K., Yasuda, O., Fukuda, M., Tokutomi, Y., Dong, Y., Ogawa, H., & Kim‐Mitsuyama, S. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.012 · Cited by 36
The discovery of endothelium-dependent contraction: The legacy of Paul M. Vanhoutte
Barton, M. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.02.013 · Cited by 39
Eucommia ulmoides leaf (EUL) extract enhances NO production in ox-LDL-treated human endothelial cells
Lee, G., Lee, H., Choi, M., Choi, A.-H., Shin, T.-S., & Chae, H. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.11.035 · Cited by 36
Perspectives on the Potential Benefits of Antihypertensive Peptides towards Metabolic Syndrome
Jahandideh, F., & Wu, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062192 · Cited by 36
“GMP mediates vasodilatation by decreasing smooth muscle tone through a reduction in the concentration of intracellular Ca2+ or reduced sensitivity to this ion [38,39].”
Background
Protein O‐GlcNAcylation in the heart
Ng, Y. H., Okolo, C. A., Erickson, J. R., Baldi, J. C., & Jones, P. P. (2021) · Acta Physiologica · doi:10.1111/apha.13696 · Cited by 36
Skeletal Muscle Nitrate as a Regulator of Systemic Nitric Oxide Homeostasis
Piknova, B., Schechter, A. N., Park, J. W., Vanhatalo, A., & Jones, A. M. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000272 · Cited by 38
Accelerated atherosclerosis in rheumatoid arthritis: a systematic review
Raj, R., Thomas, S., & Gorantla, V. R. (2022) · F1000Research · doi:10.12688/f1000research.112921.1 · Cited by 50
Effects of dietary sodium on reactive oxygen species formation and endothelial dysfunction in low-density lipoprotein receptor-deficient mice on high-fat diet
Ketonen, J., & Mervaala, E. M. A. (2008) · Heart and Vessels · doi:10.1007/s00380-008-1066-5 · Cited by 36
Superoxide Generation from Nitric Oxide Synthases
Xia, Y. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1733 · Cited by 36
“Indeed, supplementation with BH 4 or its precursors has been reported to improve endothelial function in a variety of cardiovascular disease models (12, 22, 33).”
Perspectives of Targeting mTORC1–S6K1 in Cardiovascular Aging
Ming, X., Montani, J., & Yang, Z. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00005 · Cited by 36
Plasma Kallikrein Inhibitors in Cardiovascular Disease
Kolte, D. S., & Shariat‐Madar, Z. (2015) · Cardiology in Review · doi:10.1097/crd.0000000000000069 · Cited by 36
“However, NO reacts with O 2 •− to produce ONOO, which uncouples endothelial NO synthase, transforming it from a protective enzyme to a contributor to oxidative stress.(152) HKa produced as a result of HK cleavage by plasma kallikrein increases ROS production in a concentrationdependent manner resulting in accelerated…”
Background

Authors: Förstermann, U., & Münzel, T.
Affiliations: From the Departments of Pharmacology (U.F.) and Internal Medicine II (Cardiology) (T.M.), Johannes Gutenberg University Hospitals, Mainz, Germany.
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-04-04
Volume: 113
Issue: 13
Pages: 1708-1714
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.105.602532
OpenAlex: W2146190354
Cited by: 1,957
References: 67
Citations by year: 2026: 93 · 2025: 76 · 2024: 99 · 2023: 86 · 2022: 110 · 2021: 113 · 2020: 110 · 2019: 89 · 2018: 105 · 2017: 105 · 2016: 117 · 2015: 101 · 2014: 123 · 2013: 98 · 2012: 85
FWCI: 62.52
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords: endothelial nitric oxide synthase, nitric oxide, tetrahydrobiopterin, eNOS uncoupling, NADPH oxidase, reactive oxygen species, superoxide, peroxynitrite, oxidative stress, cardiovascular risk factors, hypertension, hypercholesterolemia, diabetes mellitus, smoking, folic acid, vitamin C, L-arginine
MeSH terms: Animals, Endothelium, Vascular, Humans, Nitric Oxide, Vascular Diseases, Reactive Oxygen Species, Oxidative Stress, Nitric Oxide Synthase Type III

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Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace

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