Cited by 770Nitric Oxide and Endothelin EffectsProtein Kinase Regulation and GTPase SignalingCardiovascular Health and Disease Prevention

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.

Phosphorylation of Thr 495 Regulates Ca 2+ /Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity

Fleming, Ingrid, Fisslthaler, Beate, Dimmeler, Stefanie, Kemp, Bruce E., Busse, Rudi·2001·Circulation Research

DOI 10.1161/hh1101.092677

Open this paper in CoChat — free account

Abstract

Abstract —The activity of the endothelial nitric oxide synthase (eNOS) can be regulated independently of an increase in Ca 2+ by the phosphorylation of Ser 1177 but results only in a low nitric oxide (NO) output. In the present study, we assessed whether the agonist-induced (Ca 2+ -dependent, high-output) activation of eNOS is associated with changes in the phosphorylation of Thr 495 in the calmodulin (CaM)-binding domain. eNOS Thr 495 was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation. In the same cells, bradykinin enhanced the phosphorylation of Ser 1177 , which was maximal after 5 minutes, and abolished by the CaM-dependent kinase II (CaMKII) inhibitor KN-93. Bradykinin also enhanced the association of CaMKII with eNOS. Phosphorylation of Thr 495 was attenuated by the protein kinase C (PKC) inhibitor Ro 31-8220 and after PKC downregulation using phorbol 12-myristate 13-acetate. The agonist-induced dephosphorylation of Thr 495 was completely Ca 2+ -dependent and inhibited by the PP1 inhibitor calyculin A. Little CaM was bound to eNOS immunoprecipitated from unstimulated cells, but the agonist-induced dephosphorylation of Thr 495 enhanced the association of CaM. Mutation of Thr 495 to alanine increased CaM binding to eNOS in the absence of cell stimulation, whereas the corresponding Asp 495 mutant bound almost no CaM. Accordingly, NO production by the Ala 495 mutant was more sensitive to Ca 2+ /CaM than the aspartate mutant. These results suggest that the dual phosphorylation of Ser 1177 and Thr 495 determines the activity of eNOS in agonist-stimulated endothelial cells. Moreover, the dephosphorylation of Thr 495 by PP1 precedes the phosphorylation of Ser 1177 by CaMKII. The full text of this article is available at http://www.circresaha.org.

Integrity signals

Registry

Crossref · 10.1161/hh1101.092677

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589
Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation
Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., & Zeiher, A. M. (1999) · Nature · doi:10.1038/21224 · Cited by 3,591
Self-citation
Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase
Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C. J., Reed, R. R., & Snyder, S. H. (1991) · Nature · doi:10.1038/351714a0 · Cited by 2,354
Dynamic activation of endothelial nitric oxide synthase by Hsp90
García‐Cardeña, G., Fan, R., Shah, V. H., Sorrentino, R., Cirino, G., Papapetropoulos, A., & Sessa, W. C. (1998) · Nature · doi:10.1038/33934 · Cited by 1,029
AMP‐activated protein kinase phosphorylation of endothelial NO synthase
Chen, Z.-P., Mitchelhill, K. I., Michell, B. J., Stapleton, D., Rodríguez‐Crespo, I., Witters, L. A., Power, D. A., de Montellano, P. R. O., & Kemp, B. E. (1999) · FEBS Letters · doi:10.1016/s0014-5793(98)01705-0 · Cited by 839
Self-citation
Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase.
Nishida, K., Harrison, D. G., Navas, J. P., Fisher, A. A., Dockery, S., Uematsu, M., Nerem, R. M., Alexander, R. W., & Murphy, T. J. (1992) · Journal of Clinical Investigation · doi:10.1172/jci116092 · Cited by 735
Endothelial Nitric Oxide Synthase Is Regulated by Tyrosine Phosphorylation and Interacts with Caveolin-1
García‐Cardeña, G., Fan, R., Stern, D. F., Liu, J., & Sessa, W. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27237 · Cited by 533
Phosphorylation of Endothelial Nitric Oxide Synthase in Response to Fluid Shear Stress
Corson, M. A., James, N. L., Latta, S. E., Nerem, R. M., Berk, B. C., & Harrison, D. G. (1996) · Circulation Research · doi:10.1161/01.res.79.5.984 · Cited by 521
Calcium‐dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin
Busse, R., & Mülsch, A. (1990) · FEBS Letters · doi:10.1016/0014-5793(90)80902-u · Cited by 511
Self-citation
Molecular cloning and characterization of human endothelial nitric oxide synthase
Marsden, P. A., Schappert, K. T., Chen, H. S., Flowers, M. A., Sundell, C. L., Wilcox, J. N., Lamas, S., & Michel, T. M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)80697-f · Cited by 489

Flagged first, then by citations

Show all 38 references

Research works printed but not linked: 5

10.1161/hyp.25.2.180 · DOI
10.1161/res.79.5.984 · DOI
10.1161/res.82.6.686 · DOI
Fulton D, Gratton J-P, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt [published correction appears in Nature. 1999;400:792]. Nature. 1999;399:597–601.
10.1161/res.78.5.750 · DOI

Sorted by citations

Items 101–200 of 770

Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism
Nguyen, A., & Cai, H. “. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511011103 · Cited by 169
Bile Acid Receptor TGR5 Agonism Induces NO Production and Reduces Monocyte Adhesion in Vascular Endothelial Cells
Kida, T., Tsubosaka, Y., Hori, M., Ozaki, H., & Murata, T. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.301565 · Cited by 174
Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms
Oliveira‐Paula, G. H., Lacchini, R., & Tanus-Santos, J. E. (2015) · Gene · doi:10.1016/j.gene.2015.09.061 · Cited by 175
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript phosphorylation at Thr495 decreases enzyme activity by impairing the binding of calciumactivated calmodulin (Fleming et al., 2001).”
Background
Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone
Cho, D., Choi, Y. J., Jo, S. A., & Jo, I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309451200 · Cited by 163
Vascular actions of insulin with implications for endothelial dysfunction
Potenza, M. A., Addabbo, F., & Montagnani, M. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00297.2009 · Cited by 176
Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: A mechanism for uric acid-induced endothelial dysfunction
Li, P., Zhang, L., Zhang, M., Zhou, C., & Lin, N. (2016) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2016.2491 · Cited by 159
Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice
Massion, P. B., & Balligand, J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.025973 · Cited by 159
“…cells, stimulation with histamine or bradykinin would first lead to dephosphorylation at this threonine residue, located in the critical calmodulin binding domain, to allow the binding of calmodulin, further stabilized by the subsequent phosphorylation on serine 1177 (Fleming et al. 2001).”
Background
Molecular Mechanisms Responsible for the Atheroprotective Effects of Laminar Shear Stress
Pan, S. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2487 · Cited by 152
Novel nitric oxide signaling mechanisms regulate the erectile response
Burnett, A. L. “. (2004) · International Journal of Impotence Research · doi:10.1038/sj.ijir.3901209 · Cited by 156
Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders
Gielis, J. F., Lin, J. Y., Wingler, K., Schil, P. E. V., Schmidt, H. H. H. W., & Moens, A. L. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.018 · Cited by 158
“However, phosphorylation at Thr495 at the CaM binding domain prevents the increase in catalytic activity of eNOS by hindering the association of CaM with eNOS [22].”
Background
Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction- a novel mechanism for maintaining vascular function
Shao, Y., Cheng, Z. A., Li, X., Chernaya, V., Wang, H., & Yang, X. (2014) · Journal of Hematology & Oncology · doi:10.1186/s13045-014-0080-6 · Cited by 159
“This eNOS activation requires an elevation in intracellular free calcium concentration, formation of a complex with calmodulin and the removal of the inhibitory caveolin from the activated eNOS complex, although NO production is not affected by the components of PI3K-AKT pathway [46].”
Background
11,12-Epoxyeicosatrienoic Acid-induced Inhibition of FOXO Factors Promotes Endothelial Proliferation by Down-Regulating p27
Potente, M., Fißlthaler, B., Busse, R., & Fleming, I. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305385200 · Cited by 155
Self-citation
Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors
Kuhr, F., Lowry, J., Zhang, Y., Brovkovych, V. M., & Skidgel, R. A. (2010) · Neuropeptides · doi:10.1016/j.npep.2009.12.004 · Cited by 154
“Additionally, adenosine monophosphate (AMP)-activated protein kinase (AMPK), protein kinase G (PKG), PKA and CaM-dependent kinase II (CaMKII) can activate eNOS by phosphorylating Ser (Chen, Lin, et al., 1999; Butt et al., 2000; Fleming et al., 2001).”
Decreased Endothelial Nitric-oxide Synthase (eNOS) Activity Resulting from Abnormal Interaction between eNOS and Its Regulatory Proteins in Hypoxia-induced Pulmonary Hypertension
Murata, T., Sato, K., Hori, M., Ozaki, H., & Karaki, H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205934200 · Cited by 153
Activation of Endothelial Nitric-oxide Synthase by the p38 MAPK in Response to Black Tea Polyphenols
Anter, E., Thomas, S. R., Schulz, E., Shapira, O. M., Vita, J. A., & Keaney, J. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405547200 · Cited by 142
VEGF regulation of endothelial nitric oxide synthase in glomerular endothelial cells
Féliers, D., Chen, X., Akis, N., Choudhury, G. G., Madaio, M. P., & Kasinath, B. S. (2005) · Kidney International · doi:10.1111/j.1523-1755.2005.00575.x · Cited by 140
“Other investigators have reported that ERK inhibitors do not affect nitric oxide generation or nitric oxide–mediated relaxation of isolated arterie”
Background
Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1
Ching, L. ‐., Kou, Y. R., Shyue, S., Su, K., Wei, J., Cheng, L., Yu, Y., Pan, C.-C., & Lee, T. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr104 · Cited by 141
Novel Mechanism of Endothelial Nitric Oxide Synthase Activation Mediated by Caveolae Internalization in Endothelial Cells
Maniatis, N. A., Brovkovych, V. M., Allen, S. E., John, T. A., Shajahan‐Haq, A. N., Tiruppathì, C., Vogel, S. M., Skidgel, R. A., Malik, A. B., & Minshall, R. D. (2006) · Circulation Research · doi:10.1161/01.res.0000245187.08026.47 · Cited by 141
PKC Isozymes in Chronic Cardiac Disease: Possible Therapeutic Targets?
Churchill, E. N., Budas, G. R., Vallentin, A., Koyanagi, T., & Mochly‐Rosen, D. (2007) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.121806.154902 · Cited by 140
Targeting of Endothelial Nitric-oxide Synthase to the Cytoplasmic Face of the Golgi Complex or Plasma Membrane Regulates Akt- Versus Calcium-dependent Mechanisms for Nitric Oxide Release
Fulton, D. J., Babbitt, R. W., Zoellner, S., Fontana, J. T., Acevedo, L. M., McCabe, T. J. D., Iwakiri, Y., & Sessa, W. C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402155200 · Cited by 133
The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance
Abdelsalam, S. S., Korashy, H. M., Zeidan, A., & Agouni, A. (2019) · Biomolecules · doi:10.3390/biom9070286 · Cited by 135
Endothelial nitric oxide synthase in the microcirculation
Shu, X. H., Keller, T. C. S., Begandt, D., Butcher, J. T., Biwer, L. A., Keller, A., Columbus, L. M., & Isakson, B. E. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2021-0 · Cited by 128
Dephosphorylation of endothelial nitric oxide synthase contributes to the anti‐angiogenic effects of endostatin
Urbich, C., Reissner, A., Chavakis, E., Dernbach, E., Haendeler, J., Fleming, I., Zeiher, A. M., Kaszkin, M., & Dimmeler, S. (2002) · The FASEB Journal · doi:10.1096/fj.01-0637fje · Cited by 130
Self-citation
CaMKII as a Therapeutic Target in Cardiovascular Disease
Gaido, O. E. R., Nkashama, L. J., Schole, K. L., Wang, Q., Umapathi, P., Mesubi, O. O., Konstantinidis, K., Luczak, E. D., & Anderson, M. E. (2022) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-051421-111814 · Cited by 129
Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease
Fichtlscherer, S., Dimmeler, S., Breuer, S., Busse, R., Zeiher, A. M., & Fleming, I. (2003) · Circulation · doi:10.1161/01.cir.0000105763.51286.7f · Cited by 128
Self-citation
Exercise and Cardiovascular Health
Dimmeler, S., & Zeiher, A. M. (2003) · Circulation · doi:10.1161/01.cir.0000074244.82874.a0 · Cited by 128
Self-citation
Angiotensin-(1–7): Pharmacological properties and pharmacotherapeutic perspectives
Iusuf, D., Henning, R. H., van Gilst, W. H., & Roks, A. J. M. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.02.090 · Cited by 127
Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases
Daiber, A., Kröller‐Schön, S., Oelze, M. W., Hahad, O., Li, H., Schulz, R., Steven, S., & Münzel, T. F. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101506 · Cited by 136
The CLDN5 gene at the blood-brain barrier in health and disease
Hashimoto, Y., Greene, C., Münnich, A., & Campbell, M. (2023) · Fluids and Barriers of the CNS · doi:10.1186/s12987-023-00424-5 · Cited by 136
“Akt and calmodulin kinase phosphorylate S1177 of eNOS to activate it [126, 127] and PKA phosphorylates S633 of eNOS to up-regulate its enzymatic activity [128].”
Background
Nitric oxide signalling in the regulation of cardiovascular and platelet function
Gkaliagkousi, Ε. (2010) · Frontiers in bioscience · doi:10.2741/3828 · Cited by 124
Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass
Osto, E., Doytcheva, P., Corteville, C., Bueter, M., Dörig, C., Stivala, S., Buhmann, H., Colin, S., Rohrer, L., Hasballa, R., et al. (2015) · Circulation · doi:10.1161/circulationaha.114.011791 · Cited by 128
Endothelium-derived Hyperpolarizing Factor
Bryan, R. M., You, J., Golding, E. M., & Marrelli, S. P. (2005) · Anesthesiology · doi:10.1097/00000542-200506000-00028 · Cited by 125
Time-course of endothelial adaptation following acute and regular exercise
Haram, P. M., Adams, V., Kemi, O. J., Brubakk, A. O., Hambrecht, R., Ellingsen, Ø., & Wisløff, U. (2006) · European Journal of Cardiovascular Prevention & Rehabilitation · doi:10.1097/01.hjr.0000198920.57685.76 · Cited by 123
Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose
Dhar, A., Dhar, I., Desai, K. M., & Wu, L. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01017.x · Cited by 122
“The reduced eNOS activity is likely due to reduced BK-stimulated serine-1177 [bovine eNOS serine-1179] phosphorylation of eNOS (Dimmeler et al., 1999; Fleming et al., 2001) caused by MG (30 mM) or glucose (25 mM) (Figure 6C).”
Background
Sphingosine 1-phosphate and control of vascular tone
Dantas, A. P., Igarashi, J., & Michel, T. M. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01089.2002 · Cited by 120
“eNOS deactivation in the face of sustained Ser1179 phosphorylation may simply reflect the return of intracellular calcium concentration to baseline levels or may be consequent to phosphorylation of the enzyme at other residues (6, 15) or the intracellular translocation of the enzyme (27) leading to decreased extracell…”
Background
Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKC?
Fleming, I., MOHAMED, A., GALLE, J., Turchanowa, L., Brandes, R. P., Fißlthaler, B., & Busse, R. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.11.003 · Cited by 120
“The phosphatase that dephosphorylates Thr(495) is thought to be PP1 [12,20], but although the PP1 inhibitor, calyculin A, was able to increase Thr(495) phosphorylation in ox-LDLtreated cells, we found no evidence to suggest that its activity or expression was increased by ox-LDL.”
InfluentialSelf-citation
Endothelial nitric oxide synthase phosphorylation in treadmill‐running mice: role of vascular signalling kinases
Zhang, Q., McMillin, S. L., Tanner, J. M., Palionyte, M., Abel, E. D., & Symons, J. D. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.172916 · Cited by 117
“Furthermore, ERK 1/2 has been reported to signal downstream to phosphorylate eNOS T495, a site responsible for decreasing eNOS activity (Chen et al. 1999; Bernier et al. 2000; Boo et al. 2001, 2002; Fleming et al. 2001; Rask-Madsen & King, 2005).”
Background
Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors
Harris, M. B., Blackstone, M. A., Sood, S. G., Li, C., Goolsby, J. M., Venema, V. J., Kemp, B. E., & Venema, R. C. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00214.2004 · Cited by 117
“In addition, we and others (8, 12) have reported that agonist-induced activation of eNOS is also due, in part, to rapid dephosphorylation of Thr-497 (bovine sequence).”
BackgroundSelf-citation
eNOS Function and Dysfunction in the Penis
Musicki, B., & Burnett, A. L. “. (2006) · Experimental Biology and Medicine · doi:10.1177/153537020623100205 · Cited by 118
Prostaglandin E 2 Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase
Hristovska, A.-M., Rasmussen, L. E., Hansen, P., Nielsen, S. S., Nüsing, R. M., Narumiya, S., Vanhoutte, P. M., Skøtt, O., & Jensen, B. L. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.088948 · Cited by 116
Uric acid attenuates nitric oxide production by decreasing the interaction between endothelial nitric oxide synthase and calmodulin in human umbilical vein endothelial cells: A mechanism for uric acid-induced cardiovascular disease development
Park, J., Jin, Y. M., Hwang, S., Cho, D., Kang, D., & Jo, I. (2013) · Nitric Oxide · doi:10.1016/j.niox.2013.04.003 · Cited by 115
Physiology and pathophysiology of vascular signaling controlled by guanosine 3',5'-cyclic monophosphate-dependent protein kinase.
Birschmann, I., & Walter, U. (2004) · Acta Biochimica Polonica · doi:10.18388/abp.2004_3579 · Cited by 115
Endothelial Function in Highly Endurance-Trained Men: Effects of Acute Exercise
Rognmo, Ø., Bjørnstad, T. H., Kahrs, C. R., Tjønna, A. E., Bye, A., Haram, P. M., Stølen, T., Slørdahl, S. A., & Wisløff, U. (2008) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e31816354b1 · Cited by 112
“Interestingly, the shear stress-induced phosphorylation of eNOS is maintained (8), whereas agonist-mediated Ser 1177 phosphorylation, such as bradykinin, is only transient ( 10 ).”
Background
Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness
Soucy, K. G., Ryoo, S., Benjo, A., Lim, H. K., Gupta, G., Sohi, J. S., Elser, J., Aon, M. A., Nyhan, D., Shoukas, A. A., et al. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00138.2006 · Cited by 135
Clinical Significance of Endothelial Dysfunction in Essential Hypertension
Gkaliagkousi, Ε., Gavriilaki, E., Triantafyllou, Α., & Δούμα, Σ. (2015) · Current Hypertension Reports · doi:10.1007/s11906-015-0596-3 · Cited by 112
Plaque-prone hemodynamics impair endothelial function in pig carotid arteries
Gambillara, V., Chambaz, C., Montorzi, G., Roy, S., Stergiopulos, N., & Silacci, P. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00486.2005 · Cited by 112
Histamine Upregulates Gene Expression of Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells
Li, H., Burkhardt, C., Heinrich, U., Brausch, I., Xia, N., & Förstermann, U. (2003) · Circulation · doi:10.1161/01.cir.0000066697.19571.af · Cited by 109
Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction
Yasar, ?., Bennet, A. M., Eliasson, E., Lundgren, S., Wiman, B., Fairé, U. D., & Rane, A. (2003) · Pharmacogenetics · doi:10.1097/00008571-200312000-00002 · Cited by 111
Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall
Billaud, M., Lohman, A. W., Johnstone, S. R., Biwer, L. A., Mutchler, S. M., & Isakson, B. E. (2014) · Pharmacological Reviews · doi:10.1124/pr.112.007351 · Cited by 116
“In resting ECs, Thr495 is constitutively phosphorylated by 59AMP-activated protein kinase and PKC, antagonizing CaM binding in response to Ca-mobilizing agonists and functionally inhibiting NO synthesis by the enzyme (Fleming et al., 2001; Watts and Motley, 2009).”
BackgroundInfluential
Functional Reconstitution of Endothelial Nitric Oxide Synthase Reveals the Importance of Serine 1179 in Endothelium-Dependent Vasomotion
Scotland, R. S., Morales‐Ruiz, M., Chen, Y., Yu, J., Rudic, R. D., Fulton, D. J., Gratton, J., & Sessa, W. C. (2002) · Circulation Research · doi:10.1161/01.res.0000016506.04193.96 · Cited by 110
Src Kinase Activates Endothelial Nitric-oxide Synthase by Phosphorylating Tyr-83
Fulton, D. J., Church, J. E., Ruan, L., Li, C., Sood, S. G., Kemp, B. E., Jennings, I. G., & Venema, R. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504606200 · Cited by 112
Self-citation
Interleukin-6 Impairs the Insulin Signaling Pathway, Promoting Production of Nitric Oxide in Human Umbilical Vein Endothelial Cells
Andreozzi, F., Laratta, E., Procopio, M. C., Hribal, M. L., Sciacqua, A., Perticone, M., Miele, C., Perticone, F., & Sesti, G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01340-06 · Cited by 116
“There is evidence that PP1 is involved in dephosphorylation of Thr495, and inhibition of PP1 by calyculin-A has been shown to enhance phosphorylation of Thr495 ( 12 ).”
Background
TNF-α potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells
Yang, B., & Rizzo, V. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00758.2006 · Cited by 111
Obesity and aging: determinants of endothelial cell dysfunction and atherosclerosis
Barton, M. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0860-y · Cited by 109
The vital role for nitric oxide in intraocular pressure homeostasis
Reina‐Torres, E., Ieso, M. L. D., Pasquale, L. R., Madekurozwa, M., Sherwood, J. M., Overby, D. R., & Stamer, W. D. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100922 · Cited by 109
Heat Shock Protein 90 Transfection Reduces Ischemia-Reperfusion–Induced Myocardial Dysfunction via Reciprocal Endothelial NO Synthase Serine 1177 Phosphorylation and Threonine 495 Dephosphorylation
Kupatt, C., Dessy, C., Hinkel, R., Raake, P. W. J., Daneau, G., Bouzin, C., Boekstegers, P., & Féron, O. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000134300.87476.d1 · Cited by 108
G972R IRS-1 Variant Impairs Insulin Regulation of Endothelial Nitric Oxide Synthase in Cultured Human Endothelial Cells
Federici, M., Pandolfi, A., Filippis, E. A. D., Pellegrini, G., Menghini, R., Lauro, D., Cardellini, M., Romano, M., Sesti, G., Lauro, R., et al. (2004) · Circulation · doi:10.1161/01.cir.0000109498.77895.6f · Cited by 107
Rapid increase in endothelial nitric oxide production by bradykinin is mediated by protein kinase A signaling pathway
Bae, S. W., Kim, H. S., Nam, Y., Park, Y. S., Jo, S. A., & Jo, I. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01086-6 · Cited by 106
Circulating Microparticles from Pulmonary Hypertensive Rats Induce Endothelial Dysfunction
Tual‐Chalot, S., Guibert, C., Müller, B., Savineau, J., Andriantsitohaina, R., & Martínez, M. C. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200909-1347oc · Cited by 105
Calcium/Calmodulin-Dependent Kinase II Mediates the Phosphorylation and Activation of NADPH Oxidase 5
Pandey, D., Gratton, J.-P., Rafikov, R., Black, S. M., & Fulton, D. J. R. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.070193 · Cited by 95
Vascular Endothelium and Blood Flow
Busse, R., & Fleming, I. (2006) · Springer eBooks · doi:10.1007/3-540-36028-x_2 · Cited by 108
Self-citation
Inhibition of Endothelial Nitric Oxide Synthase Activity by Proline-Rich Tyrosine Kinase 2 in Response to Fluid Shear Stress and Insulin
Fisslthaler, B., Loot, A. E., Mohamed, A., Busse, R., & Fleming, I. (2008) · Circulation Research · doi:10.1161/circresaha.108.172072 · Cited by 99
Self-citation
Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway
Xing, S.-S., Yang, X.-Y., Zheng, T., Li, W.-J., Wu, D., Chi, J.-Y., Bian, F., Bai, X.-L., Wu, G.-J., Zhang, Y.-Z., et al. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.07.004 · Cited by 99
Nitric oxide delivery to cancer: Why and how?
Sonveaux, P., Jordan, B. F., Gallez, B., & Féron, O. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.12.018 · Cited by 103
Protein kinase C in enhanced vascular tone in diabetes mellitus
Kizub, I. V., Klymenko, K., & Soloviev, A. I. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.04.117 · Cited by 104
“As it has been shown in DM, PKC phosphorylates eNOS [117] on its inhibitory site Thr495 [123] and reduces eNOS phosphorylation on the activating Ser1177 site [124] blunting eNOS activity.”
Background
Moderate Exercise Promotes Human RBC-NOS Activity, NO Production and Deformability through Akt Kinase Pathway
Suhr, F., Brenig, J., Müller, R., Behrens, H., Bloch, W., & Grau, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045982 · Cited by 98
“The phosphorylation of RBC-NOSSer, indicating increased enzyme activity [8,19], was significantly increased after AMRT, whereas total RBC-NOS and the phosphorylation of RBC-NOS at its Thr residue, indicating inhibition of NOS enzyme activity [36], were not affected by the applied exercise intervention.”
Background
Role of CaMKII in hydrogen peroxide activation of ERK1/2, p38 MAPK, HSP27 and actin reorganization in endothelial cells
Nguyen, A., Chen, P., & Cai, H. “. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.06.061 · Cited by 98
PKCα Activates eNOS and Increases Arterial Blood Flow In Vivo
Partovian, C., Zhuang, Z., Moodie, K. L., Lin, M. I., Ouchi, N., Sessa, W. C., Walsh, K., & Simons, M. (2005) · Circulation Research · doi:10.1161/01.res.0000179775.04114.45 · Cited by 98
Activation of AMP-activated Protein Kinase by Vascular Endothelial Growth Factor Mediates Endothelial Angiogenesis Independently of Nitric-oxide Synthase
Stahmann, N., Woods, A., Spengler, K., Heslegrave, A., Bauer, R., Krause, S., Viollet, B., Carling, D., & Heller, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.108688 · Cited by 100
CaM Kinase II-dependent pathophysiological signalling in endothelial cells
Cai, H. “., Liu, D., & Garcia, J. G. N. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm010 · Cited by 97
Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension
Iwakiri, Y., Tsai, M.-H., McCabe, T. J. D., Gratton, J., Fulton, D. J., Groszmann, R. J., & Sessa, W. C. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00675.2001 · Cited by 97
Endothelial nitric oxide synthase: A potential therapeutic target for cerebrovascular diseases
Zhu, J., Song, W., Li, L., & Fan, X. (2016) · Molecular Brain · doi:10.1186/s13041-016-0211-9 · Cited by 96
Rho-kinase phosphorylates eNOS at threonine 495 in endothelial cells
Sugimoto, M., Nakayama, M., Goto, T. M., Amano, M., Komori, K., & Kaibuchi, K. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.07.030 · Cited by 96
Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways
Wang, H., Li, L., Jian-gang, J., Wang, Y., Lu, Z. Y., Bradbury, J. A., Lih, F. B., Wang, D. W., & Zeldin, D. C. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052787 · Cited by 96
“In this regard, Fleming et al. (2001b) have recently shown that EETs activate the MAPK pathway in human endothelial and vascular smooth muscle cells.”
BackgroundInfluential
Subcellular Targeting and Agonist-induced Site-specific Phosphorylation of Endothelial Nitric-oxide Synthase
Gonzalez, E., Kou, R., Lin, A. J., Golan, D. E., & Michel, T. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207299200 · Cited by 96
The Role of PPARγ in Cardiovascular Diseases
Kvandová, M., Majzúnová, M., & Dovinová, I. (2016) · Physiological Research · doi:10.33549/physiolres.933439 · Cited by 95
“…protein kinases, including PKA, PKB, PKC, AMPK, ERK and phosphatases such as protein phosphatase (PP)1 and S348 Kvandová et al. Vol. 65 PP2A in response to multiple stimuli via shear stress, growth factors, insulin, etc. (Fleming et al. 2001, Mount et al. 2007, Chen et al. 2009, Xiao et al. 2011).”
Background
Oxidative Stress and Endothelial Nitric Oxide Bioactivity
Thomas, S. R., Chen, K., & Keaney, J. F. (2003) · Antioxidants and Redox Signaling · doi:10.1089/152308603764816541 · Cited by 93
Functional role of NF-κB in expression of human endothelial nitric oxide synthase
Lee, K., Kim, J., Kwak, S.-N., Lee, K.-S., Lee, D.-K., Ha, K., Won, M., Jeoung, D., Lee, H., Kwon, Y., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.04.079 · Cited by 92
AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets
Schulz, C., Fichtlscherer, B., Kemp, B. E., Fißlthaler, B., Busse, R., & Fleming, I. (2003) · Thrombosis and Haemostasis · doi:10.1160/th03-04-0228 · Cited by 91
“Washed human platelets were lysed and Triton X-100-soluble proteins were separated by SDS-PAGE as described (16).”
MethodSelf-citation
Antihypertensive effects of oleuropein-enriched olive leaf extract in spontaneously hypertensive rats
Romero, M., Toral, M., Gómez‐Guzmán, M., Jiménez, R., Galindo, P., Sánchez, M., Olivares, M. M., Gálvez, J., & Duarte, J. (2015) · Food & Function · doi:10.1039/c5fo01101a · Cited by 91
Involvement of Ca2+/calmodulin-dependent protein kinase II in endothelial NO production and endothelium-dependent relaxation
Schneider, J., Kebir, D. E., Chéreau, C., Lanone, S., Huang, X., Roessingh, A. D. B., Mercier, J., DALL'AVA-SANTUCCI, J., & Dinh‐Xuan, A. T. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00932.2001 · Cited by 91
Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495
Lenasi, H. (2003) · Cardiovascular Research · doi:10.1016/s0008-6363(03)00505-4 · Cited by 91
Gab1, SHP2, and Protein Kinase A Are Crucial for the Activation of the Endothelial NO Synthase by Fluid Shear Stress
Dixit, M., Loot, A. E., Mohamed, A., Fißlthaler, B., Boulanger, C. M., Ceacareanu, B., Hassid, A., Busse, R., & Fleming, I. (2005) · Circulation Research · doi:10.1161/01.res.0000195611.59811.ab · Cited by 90
Self-citation
Pharmacology and Clinical Drug Candidates in Redox Medicine
Dao, V. T.-V., Casas, A. I., Maghzal, G. J., Seredenina, T., Kaludercic, N., Robledinos-Anton, N., Di Lisa, F., Stocker, R., Ghezzi, P., Jaquet, V., et al. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6430 · Cited by 88
Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase
Jeremy, J. Y., Jones, R. A., Koupparis, A. J., Hotston, M. R., Persad, R. A., Angelini, G. D., & Shukla, N. (2006) · International Journal of Impotence Research · doi:10.1038/sj.ijir.3901523 · Cited by 86
Post-translational mechanisms of endothelial nitric oxide synthase regulation by bradykinin
Venema, R. C. (2002) · International Immunopharmacology · doi:10.1016/s1567-5769(02)00185-6 · Cited by 85
Intracellular Coupling via Limiting Calmodulin
Tran, Q., Black, D. J., & Persechini, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300165200 · Cited by 84
Thrombin and histamine stimulate endothelial nitric‐oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3K‐Akt
Thors, B., Halldórsson, H., & Þorgeirsson, G. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.07.078 · Cited by 84
Emerging role of epoxyeicosatrienoic acids in coronary vascular function
Larsen, B. T., Gutterman, D. D., & Hatoum, O. A. (2006) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2006.01634.x · Cited by 83
Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells
Kida, M., Sugiyama, T., Yoshimoto, T., & Ogawa, Y. (2012) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2012.11.001 · Cited by 83
“In addition, CaM can activate CaM kinase II (CaMKII), which phosphorylates eNOS at its activating phosphoserine residue 1179 (Fleming et al., 2001).”
Background
Maternal Hypercholesterolemia in Pregnancy Associates With Umbilical Vein Endothelial Dysfunction
Leiva, A., de Medina, C. D., Salsoso, R., Sáez, T., Martín, S. S., Abarzúa, F., Farías, M., Guzmán‐Gutiérrez, E., Pardo, F., & Sobrevía, L. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.301987 · Cited by 83
Nitric oxide dysfunction in vascular endothelium and platelets: role in essential hypertension
Gkaliagkousi, Ε., Δούμα, Σ., Zamboulis, C., & Ferro, A. (2009) · Journal of Hypertension · doi:10.1097/hjh.0b013e328330e89a · Cited by 81
Possible Pathomechanisms of Sudden Infant Death Syndrome
PRANDOTA, J. (2004) · American Journal of Therapeutics · doi:10.1097/01.mjt.0000140648.30948.bd · Cited by 85
Activation of Endothelial Nitric-Oxide Synthase by Tumor Necrosis Factor-α: A Novel Pathway Involving Sequential Activation of Neutral Sphingomyelinase, Phosphatidylinositol-3′ kinase, and Akt
Barsacchi, R., Perrotta, C., Bulotta, S., Moncada, S., Borgese, N., & Clementi, E. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.4.886 · Cited by 82
Coronary Artery Vasospasm Induced by 5-fluorouracil: Proposed Mechanisms, Existing Management Options and Future Directions
Chong, J. H., & Ghosh, A. K. (2019) · Interventional Cardiology Reviews Research Resources · doi:10.15420/icr.2019.12 · Cited by 81
Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)
Coultrap, S. J., & Bayer, K. U. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.558254 · Cited by 83
Mechanism of Endothelial Nitric Oxide Synthase Phosphorylation and Activation by Thrombin
Motley, E. D., Eguchi, K., Patterson, M. M., Palmer, P. D., Suzuki, H., & Eguchi, S. (2007) · Hypertension · doi:10.1161/01.hyp.0000255954.80025.34 · Cited by 81
Periadventitial adipose tissue impairs coronary endothelial function via PKC-β-dependent phosphorylation of nitric oxide synthase
Payne, G. A., Bohlen, H. G., Dinçer, Ü. D., Borbouse, L., & Tune, J. D. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00116.2009 · Cited by 80
The Oxidative Stress Concept of Nitrate Tolerance and the Antioxidant Properties of Hydralazine
Daiber, A., Mülsch, A., Hink, U., Mollnau, H., Warnholtz, A., Oelze, M. W., & Münzel, T. F. (2005) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2005.07.030 · Cited by 84
Proteasome Inhibition Down-regulates Endothelial Nitric-oxide Synthase Phosphorylation and Function
Wei, Q., & Xia, Y. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602105200 · Cited by 79

Authors: Fleming, I., Fisslthaler, B., Dimmeler, S., Kemp, B. E., & Busse, R.
Affiliations: Goethe University Frankfurt (DE)
ORCID: Fleming, Ingrid
Fisslthaler, Beate
Dimmeler, Stefanie
Kemp, Bruce E.
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2001-06-08
Volume: 88
Issue: 11
Pages: E68-75
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/hh1101.092677
OpenAlex: W2135297555
Cited by: 770
References: 38
Citations by year: 2026: 12 · 2025: 25 · 2024: 13 · 2023: 17 · 2022: 17 · 2021: 23 · 2020: 18 · 2019: 23 · 2018: 18 · 2017: 29 · 2016: 30 · 2015: 39 · 2014: 34 · 2013: 28 · 2012: 49
FWCI: 23.32
Type: journal article
Language: en
Open access: closed
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart Foundation of Australia
Deutsche Forschungsgemeinschaft (SFB 553)
Medical Research Council
National Health and Medical Research Council
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords: endothelial nitric oxide synthase, calmodulin binding, CaMKII, PP1 phosphatase, calyculin A, bradykinin, protein kinase C, nitric oxide production, endothelial cells, dual phosphorylation, calmodulin-dependent kinase II, calmodulin
MeSH terms: Animals, Binding Sites, Bradykinin, Calcium, Calmodulin, Cells, Cultured, Coronary Vessels, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Humans, Phosphorylation, Precipitin Tests, Protein Kinase C, Proto-Oncogene Proteins, Swine, Threonine, Blotting, Western, Mutagenesis, Site-Directed, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Nitric Oxide Synthase, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Phosphorylation of Thr 495 Regulates Ca 2+ /Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks