Reactive Nitrogen Species and Fibrinogen: Exploring the Effects of Nitration on Blood Clots
Abstract
1. Introduction
2. Reactive Nitrogen Species Overview
- NO2• is a one-electron oxidant formed from NO autoxidation or ONOO− decomposition. It is also found in environmental pollutants, including cigarette smoke [37,38]. NO2• can react with NO to form N2O3 [1] or it tends to form also dinitrogen tetroxide (N2O4), which is more soluble and rapidly breaks down into NO2− and NO3− [1]. Under physiological conditions, NO2• mainly reacts with biological molecules rather than forming N2O4, especially due to its high reactivity. In cells, NO2• acts as a strong one-electron oxidant, primarily targeting thiols, ascorbate, and urate. It can also trigger lipid peroxidation and modify fatty acids or proteins [30,56].
- N2O3 arises from the equilibrium between NO and NO2•, especially under low oxygen tension. N2O3 acts as a potent nitrosating agent, capable of converting thiols to RSNO, thus playing a central role in protein S-nitrosation and transnitrosation cascades [30].
- NO2− and NO3− are often regarded as stable end-products of NO metabolism but are increasingly recognized as biologically active. In fasting individuals, plasma levels of NO3− range from 20 to 40 μM, primarily originating from the reaction between NO and oxyhemoglobin, as well as from dietary sources [61]. In contrast, plasma NO2− levels are much lower (typically 50–300 nM), due to its further conversion into NO, under hypoxic conditions, serving as a storage reservoir and participating in ischemic vasodilation. Moreover, NO2− can act as a precursor for NO2• and N2O3 in acidic or peroxidase-rich environments [62,63].
- Nitrosyl–metal complexes, such as DNICs, are formed through the interaction of NO with transition metals and thiols. These complexes function as NO reservoirs and nitrosating intermediates and are implicated in protein regulation and cytotoxicity. DNICs are particularly abundant under inflammatory and nitrosative stress conditions and have been proposed to mediate long-range nitrosative signaling [64,65].
- RSNOs, although not classic RNS themselves, are crucial downstream products of RNS action. Formed via N2O3 or through metal-catalyzed NO transfer, they regulate redox-sensitive proteins via reversible S-nitrosation of cysteine residues. This modification modulates enzyme activity, protein–protein interactions, and subcellular localization [66,67].
3. Protein Modifications Induced by RNS
3.1. Tyrosine Nitration
3.2. S-Nitrosylation
3.3. Other Modifications
4. Consequences of Nitration on Fibrinogen Molecules and Clot Morphology
4.1. Fibrinogen Tyrosine Nitration: Insights from In Vitro and In Vivo Studies
4.2. Structural and Genetic Basis of Site-Selective Fibrinogen Nitration
4.3. Site-Specific Nitration of Fibrinogen Molecule
4.4. Conformational Alterations and Clot Architecture Remodeling Induced by Nitration
5. Functional Consequences of Fibrinogen Nitration
5.1. Effects on Fibrinogen Polymerization and Fibrinolysis
5.2. Effects on Platelet and Endothelial Cell Interactions
6. Targeting RNS Production
6.1. NOX Inhibitors and Emerging Pharmacological Approaches
6.2. Natural Antioxidants Strategies
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CAD | Coronary Artery Disease |
CD | Circular Dichroism |
HMW | High Molecular Weight |
IF | Intrinsic Fluorescence |
LPS | Lipopolysaccharide |
MM | Multiple Myeloma |
Mn | Manganese |
MPO | Myeloperoxidase |
NO | Nitric Oxide |
NOX | NADPH oxidase |
NO2BF4 | Nitronium Tetrafluoroborate |
NOS | Nitric Oxide Synthase |
PTMs | Post-Translational Modifications |
RNS | Reactive Nitrogen Species |
ROS | Reactive Oxygen Species |
SIN-1 | 3-morpholinosydnonimine |
SNP | Sodium Nitroprusside |
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Author | Method | PLT Aggregation and Binding | Fibrinogen Polymerization | Fibrinogen Nitration Markers | HMW Aggregates | Fibrinogen Structural Alterations | Fiber Characteristics | Fibrin Lysis |
---|---|---|---|---|---|---|---|---|
Gole et al. (2000) [102] | Fibrinogen + 1 mM ONOO− + CO2 | + | 3nitrotyr | |||||
Pignatelli et al. (2001) [103] | Fibrinogen + 1 mM ONOO− | 3nitrotyr | ||||||
Nowak et al. (2002) [104] | Fibrinogen + 0.01, 0.1 and 1 mM ONOO− | - | 3nitrotyr | |||||
Vadseth et al. (2004) [26] | Fibrinogen + 50 mM SIN-1 + CO2 | = | + | 3nitrotyr dityr | CD | − Fiber diameter + Permeability − Density | = | |
Fibrinogen 60 nM MPO +100 μM H2O2 +100 μM NO2− | = | + | 3nitrotyr dityr | CD | − Fiber diameter + Permeability − Density | = | ||
Nowak et al. (2007) [105] | Fibrinogen + 10 μM ONOO− + CO2 | = | 3nitrotyr dityr PC | + | ||||
Fibrinogen + 100 or 1000 μM ONOO− + CO2 | - | 3nitrotyr dityr PC | + | |||||
Ponczek et al. (2008) [106] | Fibrinogen + 0.01 μM NO2BF4 | + | 3nitrotyr PC | |||||
Fibrinogen + 0.1 or 1 μM NO2BF4 | - | 3nitrotyr PC | ||||||
Bijak et al. (2012) [107] | Fibrinogen + 1 μM ONOO− | + | 3nitrotyr | + | ||||
Fibrinogen + 10 μM or higher ONOO− | - | 3nitrotyr | + | |||||
Bijak et al. (2013) [108] | Fibrinogen + 100 μM ONOO− | - | 3nitrotyr | + | ||||
Ding et al. (2014) [109] | Fibrinogen + 8.7 μM ONOO− + manganese | - | 3nitrotyr | IF | ||||
Ill-Raga et al. (2015) [110] | Fibrinogen + 100 μM SIN-1 | 3nitrotyr | IF | |||||
Fibrinogen + 10 mM SNP + 50 μM H2O2 | - | - | + stiffness | - | ||||
Helms et al. (2017) [111] | Fibrinogen + 5 μM NO donor ProliNONOate | - | 3nitrotyr PC | + Fiber diameter − Density | ||||
Marchelak et al. (2021) [112] | Fibrinogen + 100 μM ONOO− | 3nitrotyr | + | IF | ||||
Rutkowska et al. (2021) [113] | Fibrinogen + 100 μM ONOO− | 3nitrotyr | + | |||||
Medeiros et al. (2021) [114] | Fibrinogen + 200, 100 and 10 mol of ONOO− per mole of fibrinogen | 3nitrotyr | ||||||
Farhana et al. (2024) [115] | Fibrinogen + 10 μM ONOO− | PC | IF UV spectrum | |||||
Gole et al. (2000) [102] | Plasma from ARDS patients | 3nitrotyr | ||||||
Pignatelli et al. (2001) [103] | Plasma from lung cancer patients and smokers | 3nitrotyr | ||||||
Vadseth et al. (2004) [26] | Plasma from CAD patients | 3nitrotyr | ||||||
Fibrinogen from CAD patients | + | 3nitrotyr | ||||||
Parastatidis et al. (2008) [116] | Fibrinogen from smokers <25 μmol nitrotyr/mol tyr | + | 3nitrotyr | = Fiber diameter + stiffness | - | |||
Fibrinogen from smokers 25–50 μmol nitrotyr/mol tyr | + | 3nitrotyr | − Density (Cluster of fibrin) = Fiber diameter + stiffness | - | ||||
Fibrinogen from smokers >50 μmol nitrotyr/mol tyr | + | 3nitrotyr | − Density (Cluster of fibrin) = Fiber diameter + stiffness | - | ||||
Heffron et al. (2009) [117] | Plasma from volunteers receiving 1 ng/kg LPS (endotoxemia) | + | 3nitrotyr | |||||
Martinez et al. (2012) [28] | Plasma from VTE patients | 3nitrotyr | ||||||
Ill-Raga et al. (2015) [110] | Plasma from ischemic stroke patients | 3nitrotyr | IF | |||||
Nowak et al. (2017) [118] | Fibrinogen from MM patients | 3nitrotyr PC | ||||||
Medeiros et al. (2021) [114] | Fibrinogen from ischemic stroke patients | 3nitrotyr |
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Nencini, F.; Borghi, S.; Giurranna, E.; Barbaro, I.; Taddei, N.; Fiorillo, C.; Becatti, M. Reactive Nitrogen Species and Fibrinogen: Exploring the Effects of Nitration on Blood Clots. Antioxidants 2025, 14, 825. https://doi.org/10.3390/antiox14070825
Nencini F, Borghi S, Giurranna E, Barbaro I, Taddei N, Fiorillo C, Becatti M. Reactive Nitrogen Species and Fibrinogen: Exploring the Effects of Nitration on Blood Clots. Antioxidants. 2025; 14(7):825. https://doi.org/10.3390/antiox14070825
Chicago/Turabian StyleNencini, Francesca, Serena Borghi, Elvira Giurranna, Ilenia Barbaro, Niccolò Taddei, Claudia Fiorillo, and Matteo Becatti. 2025. "Reactive Nitrogen Species and Fibrinogen: Exploring the Effects of Nitration on Blood Clots" Antioxidants 14, no. 7: 825. https://doi.org/10.3390/antiox14070825
APA StyleNencini, F., Borghi, S., Giurranna, E., Barbaro, I., Taddei, N., Fiorillo, C., & Becatti, M. (2025). Reactive Nitrogen Species and Fibrinogen: Exploring the Effects of Nitration on Blood Clots. Antioxidants, 14(7), 825. https://doi.org/10.3390/antiox14070825