ArticleBiochemistry2010
Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitric oxide synthase: transition from reversible to irreversible enzyme inhibition.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 108 citations in OpenAlex.
- Microvesicle-Derived Redox Signatures as Mediators of Endothelial Dysfunction in Diabetes.International journal of molecular sciences · 2026Article
- The Janus face of L-arginine supplementation in cardiovascular health and aging exploration of underlying mechanisms.Frontiers in aging · 2026Review
- MicroRNA-Mediated Regulation of Vascular Endothelium: From Pro-Inflammation to Atherosclerosis.International journal of molecular sciences · 2025Review
- Prolonged L-NAME exposure changes the vasodilator factor from NO to HVascular pharmacology · 2024Article
- BH4 supplementation reduces retinal cell death in ischaemic retinopathy.Scientific reports · 2023Article
- Chronic anemia is associated with systemic endothelial dysfunction.Frontiers in cardiovascular medicine · 2023Article
- The Role of Ferroptosis in Blood-Brain Barrier Injury.Cellular and molecular neurobiology · 2023Review
- A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells.International journal of molecular sciences · 2022Review
- Electronic cigarette exposure causes vascular endothelial dysfunction due to NADPH oxidase activation and eNOS uncoupling.American journal of physiology. Heart and circulatory physiology · 2022Article
- Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction.JACC. Basic to translational science · 2021Article
- Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.Nature communications · 2021Article
- Long-term electronic cigarette exposure induces cardiovascular dysfunction similar to tobacco cigarettes: role of nicotine and exposure duration.American journal of physiology. Heart and circulatory physiology · 2021Article
- Vascular Dysfunction in Diabetes and Obesity: Focus on TRP Channels.Frontiers in physiology · 2021Review
- Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction.American journal of physiology. Heart and circulatory physiology · 2020Article
- Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases.Oxidative medicine and cellular longevity · 2020Review
- Tetramethoxystilbene-Loaded Liposomes Restore Reactive-Oxygen-Species-Mediated Attenuation of Dilator Responses in Rat Aortic Vessels Ex vivo.Molecules (Basel, Switzerland) · 2019Article
- Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?International journal of molecular sciences · 2019Review
- Sex, Oxidative Stress, and Hypertension: Insights From Animal Models.Physiology (Bethesda, Md.) · 2019Review
- Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?Metabolic brain disease · 2019Review
- Genetic deletion of CD38 confers post-ischemic myocardial protection through preserved pyridine nucleotides.Journal of molecular and cellular cardiology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Endothelial nitric oxide synthase (eNOS) is an important regulator of vascular and cardiac function. Peroxynitrite (ONOO(-)) inactivates eNOS, but questions remain regarding the mechanisms of this process. It has been reported that inactivation is due to oxidation of the eNOS zinc-thiolate cluster, rather than the cofactor tetrahydrobiopterin (BH(4)); however, this remains highly controversial. Therefore, we investigated the mechanisms of ONOO(-)-induced eNOS dysfunction and their dose dependence. Exposure of human eNOS to ONOO(-) resulted in a dose-dependent loss of activity with a marked destabilization of the eNOS dimer. HPLC analysis indicated that both free and eNOS-bound BH(4) were oxidized during exposure to ONOO(-); however, full oxidation of protein-bound biopterin required higher ONOO(-) levels. Additionally, ONOO(-) triggered changes in the UV/visible spectrum and heme content of the enzyme. Preincubation of eNOS with BH(4) decreased dimer destabilization and heme alteration. Addition of BH(4) to the ONOO(-)-destabilized eNOS dimer only partially rescued enzyme function. In contrast to ONOO(-) treatment, incubation with the zinc chelator TPEN with removal of enzyme-bound zinc did not change the eNOS activity or stability of the SDS-resistant eNOS dimer, demonstrating that the dimer stabilization induced by BH(4) does not require zinc occupancy of the zinc-thiolate cluster. While ONOO(-) treatment was observed to induce loss of Zn binding, this cannot account for the loss of enzyme activity. Therefore, ONOO(-)-induced eNOS inactivation is primarily due to oxidation of BH(4) and irreversible destruction of the heme/heme center.
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Registered trials
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