ArticlePloS one2014
Endothelial nitric oxide synthase dimerization is regulated by heat shock protein 90 rather than by phosphorylation.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 48 citations in OpenAlex.
- Protective Effect of Natural Phenolic Acids, Rosmarinic Acid and Salvianolic Acid, Against Diabetic Atherosclerosis.International journal of molecular sciences · 2026Review
- Sex-Specific Cardiovascular Protection in Developing Metabolic Syndrome: The Role of AMPK.Antioxidants (Basel, Switzerland) · 2025Article
- The mitochondrial redistribution of ENOS is regulated by AKT1 and dimer status.Nitric oxide : biology and chemistry · 2024Article
- Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS.International journal of molecular sciences · 2024Article
- Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.International journal of molecular sciences · 2023Review
- Clinical Applications for Gasotransmitters in the Cardiovascular System: Are We There Yet?International journal of molecular sciences · 2023Review
- The damaging duo: Obesity and excess dietary salt contribute to hypertension and cardiovascular disease.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2023Review
- Role of Chrononutrition in the Antihypertensive Effects of Natural Bioactive Compounds.Nutrients · 2022Review
- Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo.Science advances · 2022Article
- Circulating microparticles are associated with plaque burden and cause eNOS uncoupling in patients with carotid atherosclerosis.Frontiers in pharmacology · 2022Article
- Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies.International journal of molecular sciences · 2021Article
- Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction.JACC. Basic to translational science · 2021Article
- Fetal High-Density Lipoproteins: Current Knowledge on Particle Metabolism, Composition and Function in Health and Disease.Biomedicines · 2021Review
- Obesity-Related Changes in High-Density Lipoprotein Metabolism and Function.International journal of molecular sciences · 2020Review
- Heat shock protein 90 enhances the electron transfer between the FMN and heme cofactors in neuronal nitric oxide synthase.FEBS letters · 2020Article
- Mathematical Model Predicts Effective Strategies to Inhibit VEGF-eNOS Signaling.Journal of clinical medicine · 2020Article
- New Insights Into Heat Shock Protein 90 in the Pathogenesis of Pulmonary Arterial Hypertension.Frontiers in physiology · 2020Review
- Vitamin D attenuates cerebral artery remodeling through VDR/AMPK/eNOS dimer phosphorylation pathway after subarachnoid hemorrhage in rats.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2019Article
- Maternal Smoking Highly Affects the Function, Membrane Integrity, and Rheological Properties in Fetal Red Blood Cells.Oxidative medicine and cellular longevity · 2019Article
- Age-Dependent Oxidative Stress Elevates Arginase 1 and Uncoupled Nitric Oxide Synthesis in Skeletal Muscle of Aged Mice.Oxidative medicine and cellular longevity · 2019Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Endothelial nitric oxide synthase (eNOS) is a multifunctional enzyme with roles in diverse cellular processes including angiogenesis, tissue remodeling, and the maintenance of vascular tone. Monomeric and dimeric forms of eNOS exist in various tissues. The dimeric form of eNOS is considered the active form and the monomeric form is considered inactive. The activity of eNOS is also regulated by many other mechanisms, including amino acid phosphorylation and interactions with other proteins. However, the precise mechanisms regulating eNOS dimerization, phosphorylation, and activity remain incompletely characterized. We utilized purified eNOS and bovine aorta endothelial cells (BAECs) to investigate the mechanisms regulating eNOS degradation. Both eNOS monomer and dimer existed in purified bovine eNOS. Incubation of purified bovine eNOS with protein phosphatase 2A (PP2A) resulted in dephosphorylation at Serine 1179 (Ser1179) in both dimer and monomer and decrease in eNOS activity. However, the eNOS dimer∶monomer ratio was unchanged. Similarly, protein phosphatase 1 (PP1) induced dephosphorylation of eNOS at Threonine 497 (Thr497), without altering the eNOS dimer∶monomer ratio. Different from purified eNOS, in cultured BAECs eNOS existed predominantly as dimers. However, eNOS monomers accumulated following treatment with the proteasome inhibitor lactacystin. Additionally, treatment of BAECs with vascular endothelial growth factor (VEGF) resulted in phosphorylation of Ser1179 in eNOS dimers without altering the phosphorylation status of Thr497 in either form. Inhibition of heat shock protein 90 (Hsp90) or Hsp90 silencing destabilized eNOS dimers and was accompanied by dephosphorylation both of Ser1179 and Thr497. In conclusion, our study demonstrates that eNOS monomers, but not eNOS dimers, are degraded by ubiquitination. Additionally, the dimeric eNOS structure is the predominant condition for eNOS amino acid modification and activity regulation. Finally, destabilization of eNOS dimers not only results in eNOS degradation, but also causes changes in eNOS amino acid modifications that further affect eNOS activity.
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