This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Relationship: 2779
Title
Energy Deposition leads to Altered, Nitric Oxide Levels
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Deposition of energy leads to vascular remodeling | non-adjacent | High | Low | Vinita Chauhan (send email) | Open for citation & comment |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | Moderate |
Female | Low |
Unspecific | Low |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | Moderate |
Juvenile | Moderate |
Key Event Relationship Description
Deposition of energy from irradiation can affect nitric oxide (NO), a diffusible signaling molecule responsible for vasodilation (Dong et al., 2020; Mitchell et al., 2019; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). NO activity is regulated by nitric oxide synthase (NOS) enzymes, which can be affected by NOS protein concentrations and cofactors tetrahydobiopterin (BH4), nicotinamide adenine dinucleotide phosphate (NADPH) and Ca2+ (Luiking, Engelen & Deutz, 2010). The deposition of energy can alter certain pathways involving NO and therefore indirectly alter NO levels. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway, the RhoA/Rho kinase (ROCK) pathway, the renin-angiotensin-aldosterone system (RAAS), and the acidic sphingomyelinase/ceramide pathway can influence NO levels (Hemmings & Restuccia 2012; Millatt, Abdel-Rahman & Siragy, 1999; Nagane et al., 2021; Soloviev & Kizub, 2019; Yao et al., 2010).
Deposition of energy can alter NO levels through radiolysis and the direct formation of reactive oxygen species (ROS) (Azzam, Jay-Gerin & Pain, 2013). An increase in ROS and reactive nitrogen species (RNS) can influence NO levels; however, the involvement of RNS in NO production has not been strongly demonstrated in literature (Nagane et al., 2021). ROS acts as a modulator for the relationship between energy deposition leading to altered NO levels. Following ionizing radiation (IR) exposure, there are various enzymes and immune cells involved with indirectly increasing ROS, thereby influencing NO levels (Powers & Jackson, 2008; Soloviev & Kizub, 2019; Vargas-Mendoza et al., 2021).
Evidence Collection Strategy
The strategy for collating the evidence on radiation stressors to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.
Evidence Supporting this KER
Overall weight of evidence: High
Biological Plausibility
The biological plausibility surrounding the connection between deposition of energy and altered NO levels is well-supported by reviews in the literature and mechanistic understanding. NO is a diffusible molecule produced by endothelial cells (Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). The enzyme NOS produces NO and can be used as a proxy to measure NO levels. eNOS and iNOS are common endpoints for assessing NO levels. Changes in eNOS phosphorylation (p-eNOS) can also indicate NO levels, with phosphorylation at serine 1177 increasing eNOS activity and phosphorylation at threonine 495 decreasing eNOS activity (Nagane et al., 2021). The deposition of energy from IR can indirectly lead to changes in NO levels through various pathways (Nagane et al., 2021; Soloviev & Kizub, 2019).
NO levels can be altered by deposition of energy through ROS. ROS can be produced directly through the radiolysis of water or indirectly through the mitochondrial electron transport chain (ETC) and various enzymes and immune cells (Azzam, Jay-Gerin & Pain, 2013; Powers & Jackson, 2008; Soloviev & Kizub, 2019; Vargas-Mendoza et al., 2021). NO bioavailability is reduced through the molecule’s reaction with ROS that produces peroxynitrite, or oxidation of the NOS cofactor BH4. This uncouples NOS causing it to produce ROS instead of NO, further driving down NO bioavailability (Forrester et al., 2019; Soloviev & Kizub, 2019). NO can also increase as a result of deposition of energy through activation of iNOS during oxidative stress (Nathan & Xie, 1994). However, this additional NO reacts with ROS to form peroxynitrite (Nagane et al., 2021; Soloviev & Kizub, 2019). The reaction of ROS with NO produces the RNS peroxynitrite, which can also further oxidize BH4 and uncouple NOS, resulting in further NO reduction (Soloviev & Kizub, 2019).
Deposition of energy can also alter NO levels by activating signaling pathways involved in NO regulation. Under normal conditions, the PI3K/Akt pathway can activate NOS through phosphorylation (Hemmings & Restuccia 2012; Nagane et al., 2021). The RhoA/ROCK pathway prevents both the expression and phosphorylation of NOS (Yao et al., 2010). Furthermore, the RAAS pathway can increase the production of ROS through NADPH oxidase (NOX), which causes decreased NO (Nguyen Dinh Cat et al., 2013). Additionally, the RAAS pathway can activate NOS as a countermeasure for vasoconstriction (Millatt, Abdel-Rahman & Siragy, 1999). Lastly, the acidic sphingomyelinase/ceramide pathway can also activate NOX, resulting in lower NO levels (Soloviev & Kizub, 2019). Deposition of energy from IR can change these pathways through oxidative stress and changes in protein expression, which results in altered NO levels (Schmidt-Ullrich et al., 2000).
Empirical Evidence
The empirical evidence supporting this KER was collected from research using both in vivo and in vitro models. The use of X-rays and gamma rays as stressors with doses ranging from 0.05 Gy to 60 Gy demonstrates the relationship between deposition of energy and altered NO levels. The dose, dose rate, and radiation type will all influence the level of energy deposition and therefore of NO production, but insufficient evidence exists to quantify the relationship between these factors and NO production. Human coronary artery endothelial cells (HCAECs) (Azimzadeh et al. 2017), human aortic endothelial cells (HAoECs) (Azimzadeh et al., 2021), human umbilical vein endothelial cells (HUVECs) (Hong et al. 2013; Sakata et al., 2015; Sonveaux et al., 2003), bovine aortic endothelial cells (BAECs) (Hirakawa et al., 2002; Sonveaux et al., 2003), tumor models (Sonveaux et al., 2003), cardiac microvascular endothelial cells and serum (Azimzadeh et al. 2015), as well as in vivo rat pulmonary arterioles (Fuji et al., 2016), Wistar albino rat heart tissue and serum (Abdel-Mageid & Shedid, 2019), B6J mice aortic endothelium (Hamada et al., 2020; Hamada et al., 2021), WAG/RijCmcr rat heart tissue (Baker et al., 2009), and serum from the abdominal inferior vena cava (Ohta et al., 2007) were the models used in these studies. Both direct NO measures, such as ELISA assay, and indirect NO measures, such as eNOS, iNOS, citrulline (NOS product) and NOx (nitrite and nitrate, NO metabolites) levels and activity, were used to determine changes in NO levels following energy deposition.
Dose Concordance
Evidence shows concordant changes in NO levels and deposition of energy. The study by Dias et al. (2018) showed varying changes to eNOS after chronic gamma irradiation, with a general trend of decreasing eNOS expression with increasing energy deposition (i.e., at 0.5, 1, and 2 Gy). Similarly, HUVECs exposed to gamma irradiation showed slightly lower eNOS levels at 12.5 Gy than at 10 Gy (Sadhukhan et al., 2020). X-ray irradiation of mouse cardiac microvascular endothelial cells showed 0.6 and 0.2-fold decreases in p-eNOS at 8 and 16 Gy, respectively (Azimzadeh et al., 2015). X-ray irradiation of mouse blood serum showed NO decreased 0.3-fold and 0.2-fold following 8 Gy and 16 Gy X-ray irradiation, respectively (Azimzadeh et al., 2015).
In contrast, BAECs and HUVECs irradiated with X-rays showed a trend of increasing eNOS expression and activation from 2 to 20 Gy (Sonveaux et al., 2003). Using similar doses of X-rays also showed that NOx increased dose-dependently from 1 to 20 Gy and reached a maximum increase of 10-fold (Sakata et al., 2015). Other high X-ray doses from 19.6 to 31.5 Gy on mice showed about a 2-fold increase in serum nitrate concentration, which had a general increasing trend at larger doses (Ohta et al., 2017). In BAECs, eNOS expression did not significantly change from 1 to 60 Gy of X-rays, while iNOS expression increased to 6% of GAPDH expression after 1 Gy, 26% after 2 Gy and remained around 40% of GAPDH expression from 10 to 60 Gy (Hirakawa et al., 2002).
Many studies do not examine this relationship at multiple doses. After 0.5 Gy X-ray irradiation of HCAECs, p-eNOS and NO were both decreased (Azimzadeh et al., 2017). HUVECs irradiated with 4 Gy X-rays showed increases in iNOS and nitrotyrosine (peroxynitrite biomarker) levels (Hong et al., 2013). eNOS levels decreased in mouse aortic endothelial cells when exposed to 5 Gy gamma and X-ray irradiation at various acute and chronic regimens (Hamada et al., 2020; Hamada et al., 2021; Hamada et al., 2021). Rat cardiac and serum NOx increased as a response to 8 Gy gamma irradiation (Abdel-Mageid & Shedid, 2019). Total body irradiation (TBI) of rats with 10 Gy X-rays resulted in a decrease in eNOS, iNOS and NOx levels (Baker et al., 2009). Both cardiac eNOS and serum NO decreased to 73% and 63%, respectively, following 16 Gy X-ray irradiation (Azimzadeh et al., 2021).
Time Concordance
There is evidence that a change in NO levels occurs after energy deposition (i.e., irradiation) occurred. HUVECs irradiated with 4 Gy X-rays displayed an increase in nitrotyrosine (peroxynitrite biomarker) at 6 hours post-irradiation (Hong et al., 2013). They also showed increased iNOS after 1.5, 3, and 6 hours (Hong et al., 2013). Following a 26 Gy X-ray irradiation of mice, serum nitrate concentration showed a maximum increase after 3h, followed by a return to pre-irradiation levels at 12 h and 24 h post-irradiation (Ohta et al., 2007). As well, in HUVECs, 10 and 12 Gy gamma rays led to decreased eNOS levels after 4 and 24 h (Sadhukhan et al., 2020). BAECs and HUVECs irradiated with 6 Gy X-rays did not exhibit significant changes in eNOS 1-6 h post-irradiation, but eNOS increased after 12, 24, and 48 hours (Sonveaux et al., 2003)
HUVECs irradiated with 10 Gy X-rays also had no change in eNOS levels over 72 h, while p-eNOS (Ser1177) increased consistently over 72 h, p-eNOS (Thr495) decreased after 6 h and returned to initial levels after 72 h, iNOS did not change other than a non-significant increased after 24 h, citrulline increased after 6 h and remained the same for 72 h and NOx increased over 72 h (Sakata et al., 2015). After 2 Gy X-ray irradiation of BAECs, eNOS expression did not significantly change from 0-120 h, iNOS expression increased to a maximum 6 h post-irradiation and NO increased to a maximum 12 h (Hirakawa et al., 2002).
Following 0.5 Gy X-ray irradiation of HCAECs, NO was not significantly lower after 1 day, while the 7 and 14 day time-points showed significant decreases (Azimzadeh et al., 2017). In human aortic endothelial cells, acute gamma radiation consistently showed decreased eNOS at each time-point up to 16 days after irradiation, while chronic irradiation decreased eNOS levels 1 and 4 days post-irradiation (Dias et al., 2018).
Finally, eNOS expression was lower 1, 3, and 6 months post-irradiation of mice aortic endothelial cells with 5 Gy gamma rays (Hamada et al., 2020).
Essentiality
Altered NO levels can occur due to a deposition of energy in the form of ionizing radiation. Since deposited energy initiates events immediately, the removal of deposited energy also supports the essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects. Deposition of energy cannot be blocked by chemicals, but radiation could be shielded. Currently, no studies show the effect of shielding on this relationship.
Uncertainties and Inconsistencies
- Due to the high reactivity of NO, it can be difficult to directly measure it (Luiking, Engelen & Deutz, 2010). The inconsistencies in NO levels may be attributed to the challenges in measuring NO, such as its availability in cell (Azimzadeh et al., 2017; Hirakawa et al., 2002; Hong et al., 2013; Sakata et al., 2015; Sonveaux et al., 2003), serum (Abdel-Magied & Shedid,. 2019; Azimzadeh et al. 2015; Ohta et al., 2007) or tissue (Abdel-Magied & Shedid, 2019; Baker et al., 2009; Fuji et al., 2016; Hamada et al., 2020), its homeostasis with ROS, and its relationship to nitrosylation as accumulated damage and whether p-eNOS/eNOS is being measured.
Known modulating factors
Modulating factor |
Details |
Effects on the KER |
References |
Drug |
ZnO-NPs (Zinc oxide nanoparticles that act as antioxidants) |
Treatment with ZnO-NPs after irradiation returned nitrite/nitrate levels closer to control |
Abdel-Magied & Shedid, 2019 |
Drug |
Fenofibrate (PPARα agonist) |
Treatment with Fenofibrate eliminated the radiation-induced decrease in NO levels. |
Azimzadeh et al., 2021 |
Drug |
Atorvastatin |
Treatment significantly increased eNOS levels |
Sadhukhan et al., 2020 |
Drug |
Gamma tocotrienol |
Treatment eliminated the radiation-induced decrease in eNOS levels. |
Sadhukhan et al., 2020 |
Drug |
Geranylgeranyl transferase I inhibitor 298 |
Treatment eliminated the radiation-induced decrease in eNOS levels. |
Sadhukhan et al., 2020 |
Quantitative Understanding of the Linkage
Examples of quantitative understanding of the relationship are provided. All data that is represented is statistically significant unless otherwise indicated.
Response-response Relationship
Dose Concordance
Reference |
Experiment Description |
Result |
Azimzadeh et al., 2015 |
In vivo. 10-week-old mice were exposed to X-ray irradiation at either 8 or 16 Gy. Cardiac levels of NO, eNOS and p-eNOS were determined. Protein levels were measured using immunoblotting, and NO was measured using an ELISA assay. |
p-eNOS decreased 0.6-fold after 8 Gy and 0.2-fold after 16 Gy. NO decreased 0.3-fold after 8 Gy and 0.2-fold after 16 Gy. eNOS levels did not change. |
Azimzadeh et al., 2017 |
In vitro. HCAECs were irradiated with 0.5 Gy X-ray irradiation over 1 minute. Phosphorylated and total eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. Measurements were taken after 1, 7, and 14 days. |
p-eNOS/total eNOS was 0.7-fold lower than control and NO was 0.8-fold lower than control after 14 days. |
Hong et al., 2013 |
In vitro. HUVECs were irradiated with 4 Gy X-rays (2.7 Gy/min) and amounts of eNOS, iNOS and nitrotyrosine (a biomarker for peroxynitrite) were determined by western blot. Measurements were taken after 1.5, 3, and 6 hours. |
In 4 Gy irradiated HUVECs, iNOS was increased 6.6-fold and nitrotyrosine was increased 6.4-fold after 6 h. eNOS expression did not change. |
Fuji et al., 2016 |
In vivo. eNOS levels in the smooth muscle layer of 4-week-old rat pulmonary arteries were determined using immunohistochemical staining after irradiation (dose not specified). A 6.5 GeV electron beam was converted into monochromatic X-rays. Measurements were taken after 2 weeks. |
eNOS levels decreased 0.6-fold compared to control. |
Abdel-Magied & Shedid, 2019 |
In vivo. Adult male rats were irradiated with 8 Gy 137Cs gamma irradiation (0.4092 Gy/min). Serum and heart total NOx was determined with a NOx assay kit. Measurements were taken after 14 days. |
Cardiac and serum NOx increased 2 and 1.8-fold after exposure to 8 Gy, respectively. |
Hamada et al., 2022 |
In vivo. 8-week-old mice were irradiated with 5 Gy 260 kVp X-rays at 0.5 Gy/min delivered in 25 or 100 daily fractions over 42 or 152 days, respectively, or delivered as an acute single dose. As well, chronic 137Cs gamma rays (<1.4 mGy/h for 153 days) were delivered in another regimen. eNOS levels were determined by immunofluorescence. |
At 6 months after the start of irradiation, eNOS decreased 0.3-fold, 0.4-fold, and 0.4-fold following single dose irradiation, 25 fraction regimens, and 100 fraction regimens, respectively. eNOS also decreased 0.8-fold after chronic gamma ray irradiation. At 12 months after the start of irradiation, eNOS decreased 0.7-fold, 0.8-fold and 0.8-fold following acute, 25 fraction and 100 fraction regimens, respectively. |
Hamada et al., 2020 |
In vivo. 8-week-old male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min). Immunofluorescence was used to determine eNOS levels. Measurements were taken after 1, 3, and 6 months. |
6 months post-irradiation of 5 Gy, eNOS decreased by 0.3- fold. |
Baker et al., 2009 |
In vivo. Male rats were irradiated with 10 Gy X-rays (1.95 Gy/min). Western blotting was used to determine eNOS and iNOS. NOx content was determined using ozone chemiluminescence. Measurements were taken after 120 days. |
Rats exposed to 10 Gy of TBI experienced a 27% decrease in eNOS, a 29% decrease in iNOS protein, and a 20% decrease in NOx (index of NO activity). |
Sonveaux et al., 2003 |
In vitro. Levels of eNOS and p-eNOS after X-ray irradiation of BAECs and HUVECs were measured with immunoblotting at various doses (0.86 Gy/min). eNOS mRNA was also measured with RT-qPCR before and after 2 Gy-irradiated human tumour cells. |
Compared to controls, 24 h after irradiation, eNOS increased 1.3-fold after 2 Gy (not significant), 2.1-fold after 4 Gy (not significant), 3-fold after 6 and 8 Gy, 4.3-fold after 10 Gy and 3.4-fold after 20 Gy. Compared to controls, 24 h after irradiation, p-eNOS increased 1.2-fold after 2 Gy and 1.7-fold after 6 Gy. eNOS increased in human tumor cells in every patient after 2 Gy irradiation. |
Hirakawa et al., 2002 |
In vitro. BAECs were irradiated with X-rays at various doses. eNOS and iNOS were measured with semiquantitative RT-PCR and western blot. NO was measured through DAF-2, a NO-sensitive fluorescent dye after treatment with L-arginine. |
eNOS expression did not significantly change from 1-60 Gy. iNOS expression did not occur in non-irradiated samples, but increased to 6% of GAPDH expression after 1 Gy, 26% after 2 Gy and remained around 40% of GAPDH expression from 10-60 Gy. NO increased a maximum of 5.2-fold 12h after 2 Gy irradiation. |
Sakata et al., 2015 |
In vitro. HUVECs were irradiated with various doses of X-rays. eNOS, p-eNOS (Ser1177 & Thr495), iNOS, citrulline (produced by NOS with NO) and NOx levels were measured with western blots for proteins and various assay kits for molecules. |
For maximum changes after 10 Gy, eNOS expression did not significantly change, p-eNOS (Ser1177) increased 1.8-fold, p-eNOS (Thr495) decreased 0.3-fold, iNOS showed a non-significant 1.4-fold increase and citrulline increased 1.3-fold. NOx increased consistently from 1-20 Gy and showed a maximum 10-fold increase after 10 Gy. |
Ohta et al., 2007 |
In vivo. Levels of nitrate in mouse serum were measured by Griess assay after a whole-body X-ray irradiation of 6-week-old mice using various doses from 19.6 to 31.5 Gy. |
Serum nitrate concentrations increased about 2-fold from 0-31.5 Gy. |
Hamada et al., 2021 |
In vivo. Either acute or chronic doses of X-rays and 137Cs gamma rays were given to 8-week-old B6J mice, to a total 5 Gy dose. X-rays were given as a single acute dose, 25 fractions of 0.2 Gy/fraction spread over 42 days or 100 fractions of 0.05 Gy/fraction spread over 153 days all given at 0.5 Gy/min. Gamma rays were given as a single acute dose at 0.5 Gy/min or chronically at <1.4 mGy/h for 153 days. eNOS was measured through immunofluorescence. |
All regimens of X-rays and acute gamma rays led to a 0.3- to 0.4-fold decrease in eNOS levels. Chronic gamma rays led to a 0.8-fold (nonsignificant) decrease in eNOS levels. |
Azimzadeh et al., 2021 |
In vivo. 8-week-old male C57BL/6J were irradiated with an acute dose of 16 Gy X-rays. eNOS activity and NO were measured using fluorometric and Griess assays, respectively. |
16 Gy resulted in a decrease in eNOS activity to 73% in heart tissue. NO levels decreased to 63% in serum. |
Sadhukhan et al., 2020 |
In vitro. HUVECs were irradiated with various regimens and doses of 137Cs gamma radiation. eNOS levels were determined by western blot. Fractionated doses were separated by 24 h. |
At 5 doses of 2 Gy, eNOS decreased 0.2-fold. At 5 doses of 2.5 Gy, eNOS decreased 0.3-fold. At a single dose of 10 Gy, eNOS decreased 0.8-fold. At a single dose of 12 Gy, eNOS decreased 0.7-fold. |
Dias et al., 2018 |
In vitro. HAoECs were irradiated with various regimens of 60Co gamma radiation. Acute radiation was given at 1 Gy/min, while chronic radiation was given at 6 mGy/h eNOS mRNA level was determined using qPCR. Each dose was measured at different times after irradiation. |
An acute dose of 0.05 Gy led to a 0.6-fold decrease in eNOS while the chronic dose led to a 1.6-fold increase. At 0.5 Gy, the acute dose did not significantly change eNOS, while the chronic dose increased it 1.6-fold. Acute 1 Gy caused eNOS to decrease 0.5-fold without significant changes chronically. Acute 2 Gy caused a 0.3-fold decrease in eNOS without significant changes chronically. |
Time-scale
Time Concordance
Reference |
Experiment Description |
Result |
Azimzadeh et al., 2017 |
In vitro. HCAECs were irradiated with 0.5 Gy X-ray irradiation over 1 minute. Phosphorylated and total eNOS levels were determined using immunoblotting, and NO levels were determined using ELISA assay. Measurements were taken after 1, 7 or 14 days. |
1 day after 0.5 Gy irradiation, p-eNOS/total eNOS was 0.8-fold lower than control and NO did not change. After 7 days, p-eNOS/total eNOS was 0.6-fold lower than control and NO was 0.8-fold lower than control. After 14 days, p-eNOS/total eNOS was 0.7-fold lower than control and NO was 0.8-fold lower than control. |
Hong et al., 2013 |
In vitro. HUVECs were irradiated with 4 Gy X-rays (2.7 Gy/min) and amounts of iNOS and nitrotyrosine (a biomarker for peroxynitrite) were determined by western blot at various times over 6 hours. |
1.5 h after 4 Gy irradiation, iNOS 1.9-fold higher than control and nitrotyrosine did not change. After 3 h, iNOS was 2.8-fold higher than control and nitrotyrosine did not change. After 6 h, iNOS was 6.6-fold higher than control and nitrotyrosine was 6.3-fold higher than control. |
Hamada et al., 2020 |
In vivo. 8-week-old male mice were irradiated by 5 Gy 137Cs gamma rays (0.5 Gy/min). Immunofluorescence was used to determine eNOS levels. Measurements were taken after 1, 3 and 6 months. |
eNOS levels decreased 0.5-fold at 1-month post-irradiation, 0.4-fold at 3 months post-irradiation and a maximal fold decrease of 0.3-fold 6 months post-irradiation. |
Sonveaux et al., 2003 |
In vitro. Level of eNOS after X-ray irradiation of BAECs and HUVECs was measured with immunoblotting at various times. |
At 6 Gy, eNOS did not significantly change 1-6 h post-irradiation, but increased 1.8-fold after 12 h, 2-fold after 24 h and 1.5-fold after 48 h. |
Hirakawa et al., 2002 |
In vitro. BAECs were irradiated with 2 Gy X-rays at various times. eNOS and iNOS were measured with semiquantitative RT-PCR and western blotting. NO was measured through DAF-2, a NO-sensitive fluorescent dye after treatment with L-arginine. |
eNOS expression did not significantly change from 0-120 h post-irradiation. iNOS expression did not occur in non-irradiated samples but increased to a maximum 26% of GAPDH expression 6 h post-irradiation, and slowly decreased to 16% after 120 h. Similarly, NO increased a maximum of 5.2-fold after 12 h, while NO levels slowly returned after 120 h. |
Sakata et al., 2015 |
In vitro. HUVECs were irradiated with 10 Gy X-rays at various times. eNOS, p-eNOS (Ser1177 & Thr495), iNOS, citrulline (produced by NOS with NO) and NOx levels were measured with western blots for proteins and various assay kits for molecules. |
eNOS expression did not significantly change over 72 h, p-eNOS (Ser1177) increased 1.8-fold over 72 h, p-eNOS (Thr495) decreased 0.3-fold after 6 h and returned to initial levels after 72 h, iNOS did not change other than a nonsignificant 1.4-fold increased after 24 h. Citrulline increased 1.3-fold after 6 h and remained the same for 72 h. NOx increased 3.7-fold after 6 h and 5-fold after 72 h. |
Ohta et al., 2007 |
In vivo. Levels of nitrate in mouse serum were measured by Griess assay at various times after a whole-body 26 Gy X-ray irradiation of 6-week-old mice. |
Serum nitrate concentration showed a maximum increase of 2.1-fold after 3 h, followed by a return to pre-irradiation levels at 12 h and 24 h post-irradiation. |
Sadhukhan et al., 2020 |
In vitro. HUVECs were irradiated with various regimens and doses of 137Cs gamma radiation. eNOS levels were determined by western blot 4 and 24 h after irradiation. Fractionated doses were separated by 24 h. |
After the 10 Gy doses, eNOS was lowest at 4 h, but after 12 Gy it was the same at both 4 and 24 h. |
Dias et al., 2018 |
In vitro. HAoECs were irradiated with various regimens of 60Co gamma radiation. Acute radiation was given at 1 Gy/min, while chronic radiation was given at 6 mGy/h. eNOS mRNA level was determined using qPCR up to 16 days after irradiation. Each timepoint used a different dose. |
An acute dose of 0.05 Gy led to a 0.6-fold decrease in eNOS while the chronic dose led to a 1.6-fold increase 1 day post-irradiation. At 0.5 Gy, the acute dose did not significantly change eNOS, while the chronic dose increased it 1.6-fold 4 days post-irradiation. Acute 1 Gy caused eNOS to decrease 0.5-fold without significant changes chronically 8 days post-irradiation. Acute 2 Gy caused a 0.3-fold decrease in eNOS without significant changes chronically 16 days post-irradiation. |
Known Feedforward/Feedback loops influencing this KER
Not identified
Domain of Applicability
The evidence for the taxonomic applicability to humans is low as evidence comes from in vitro human cell-derived models. The relationship has been shown in vivo in mice and rats, with considerable evidence in mice. The relationship has been shown in vivo in males and is likely in females. Most in vivo studies indicate adult or adolescent animal models used. In addition, the relationship is also likely in preadolescent animals.
References
Abdel-Magied, N. and S. M. Shedid (2019), “Impact of zinc oxide nanoparticles on thioredoxin-interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma-irradiated rats”, Environmental Toxicology, Vol. 35, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/tox.22879.
Azimzadeh, O. et al. (2021), “Activation of PPARα by feno fibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome”, Biomedicines, Vol. 9/12, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/biomedicines9121845.
Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, International Journal of Radiation Biology, Vol. 93/9, Informa, London, https://doi.org/10.1080/09553002.2017.1339332.
Azimzadeh, O. et al. (2015), “Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction”, Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b.
Azzam, E. I., J. P. Jay-Gerin and D. Pain (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2011.12.012.
Baker, J. E. et al. (2009), “10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model”, International Journal of Radiation Biology, Vol. 85/12, Informa, London, https://doi.org/10.3109/09553000903264473
Dias, J. et al. (2018), “Gamma Low- Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner”, Dose-Response, Vol. 16/1, SAGE Publications, Thousand Oaks, https://doi.org/10.1177/1559325818755238.
Dong, S. et al. (2020), “Oxidative stress: A critical hint in ionizing radiation induced pyroptosis”, Radiation Medicine and Protection, Vol. 1/4, National Institute of Radiological Protection, https://doi.org/10.1016/j.radmp.2020.10.001.
Forrester, S. J. et al. (2018), “Reactive Oxygen Species in Metabolic and Inflammatory Signaling”, Circulation Research, Vol. 122/6, Lippincot Williams & Wilkins, Philadelphia, https://doi.org/10.1161/CIRCRESAHA.117.311401.
Fuji, S. et al. (2016), “Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension”, General Thoracic and Cardiovascular Surgery, Vol. 64, Springer, New York, https://doi.org/10.1007/s11748-016-0684-6.
Hamada, N. et al. (2022), “Temporal Changes in Sparing and Enhancing Dose Protraction Effects of Ionizing Irradiation for Aortic Damage in Wild-Type Mice”, Cancers, Vol. 14/14, MDPI, Basel, https://doi.org/10.3390/cancers14143319
Hamada, N. et al. (2021), “Vascular damage in the aorta of wild-type mice exposed to ionizing radiation: Sparing and enhancing effects of dose protraction”, Cancers, Vol.13/21, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/cancers13215344.
Hamada, N. et al. (2020), “Ionizing Irradiation Induces Vascular Damage in the Aorta of Wild-Type Mice”, Cancers, Vol. 12/10, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/CANCERS12103030.
Hemmings, B. A. and D. F. Restuccia (2012). “PI3K-PKB/Akt Pathway”, Cold Spring Harbor Perspectives in Biology, Vol. 4/9, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, https://doi.org/10.1101/CSHPERSPECT.A011189.
Hirakawa, M. et al. (2002), “Tumor Cell Apoptosis by Irradiation-induced Nitric Oxide Production in Vascular Endothelium”, Cancer Research, Vol. 62/5, American Association for Cancer Research, Philadelphia, pp. 1450–1457.
Hong, C. W. et al. (2013), “Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage”, Journal of Radiation Research, Vol. 54/6, Oxford University Press, Oxford, https://doi.org/10.1093/JRR/RRT066.
Ježek, P. and L. Hlavatá (2005), “Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism”, The International Journal of Biochemistry & Cell Biology, Vol. 37/12, Elsevier, Amsterdam, https://doi.org/10.1016/j.biocel.2005.05.013.
Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306
Luiking, Y. C., M. P. Engelen and N. E. Deutz (2010), “Regulation of nitric oxide production in health and disease”, Current Opinion in Clinical Nutrition and Metabolic Care, Vol. 13/1, Lippincott Williams and Wilkins Ltd, Philadelphia, https://doi.org/10.1097/MCO.0b013e328332f99d.
Millatt, L. J., E. M. Abdel-Rahman and H. M. Siragy (1999), “Angiotensin II and nitric oxide: a question of balance”, Regulatory Peptides, Vol. 81/1-3, Elsevier, Amsterdam, https://doi.org/10.1016/S0167-0115(99)00027-0.
Mitchell, A. et al. (2019), “Cardiovascular effects of space radiation: implications for future human deep space exploration”, European Journal of Preventive Cardiology Vol. 26/16, SAGE Publishing, Thousand Oaks, https://doi.org/10.1177/2047487319831497.
Nagane, M. et al. (2021), “DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases”, Journal of Radiation Research, Vol. 62/4, Oxford University Press, Oxford, https://doi.org/10.1093/JRR/RRAB032.
Nathan, C. and Q. W. Xie (1994), “Regulation of biosynthesis of nitric oxide”, Journal of Biological Chemistry, Vol. 269/19, American Society for Biochemistry and Molecular Biology, Rockville, https://doi.org/10.1016/S0021-9258(17)36703-0.
Nguyen Dinh Cat, A. et al. (2013), “Angiotensin II, NADPH Oxidase, and Redox Signaling in the Vasculature”, Antioxidants & Redox Signaling, Vol. 19/10, Mary Ann Liebert, Inc., Larchmont, https://doi.org/10.1089/ARS.2012.4641.
Ohta, S. et al. (2007), “The Role of Nitric Oxide in Radiation Damage”, Biological and Pharmaceutical Bulletin, Vol. 30/6, Pharmaceutical Society of Japan, Tokyo, https://doi.org/10.1248/bpb.30.1102.
Powers, S. K. and M. J. Jackson (2008), “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production”, Physiological Reviews, Vol. 88/4, The American Physiological Society, Rockville, https://doi.org/10.1152/physrev.00031.2007
Sadhukhan, R. et al. (2020), “Fractionated radiation suppresses Kruppel-like factor 2 pathway to a greater extent than by single exposure to the same total dose”, Scientific Reports, Vol. 10/1, Nature Portfolio, London, https://doi.org/10.1038/s41598-020-64672-3.
Sakata, K. et al. (2015), “Roles of ROS and PKC-βII in ionizing radiation-induced eNOS activation in human vascular endothelial cells”, Vascular Pharmacology, Vol. 70, Elsevier, Amsterdam, https://doi.org/10.1016/j.vph.2015.03.016.
Schmidt-Ullrich, R. K. et al. (2000), “Signal Transduction and Cellular Radiation Responses”, Radiation Research, Vol. 153, Radiation Research Society, Bozeman, https://doi.org/10.1667/0033-7587(2000)153[0245:STACRR]2.0.CO;2.
Soloviev, A. I. and I.V. Kizub (2019), “Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction”, Biochemical pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019.
Sonveaux, P. et al. (2003), “Irradiation-induced Angiogenesis through the Up-Regulation of the Nitric Oxide Pathway: Implications for Tumor Radiotherapy”, Cancer Research, Vol. 63/5, American Association for Cancer Research, Philadelphia, pp. 1012–1019.
Vargas-Mendoza, N. et al. (2021), “Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition”, Life, Vol. 11/11, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/life11111269.
Wang, Y., M. Boerma and D. Zhou (2016), “Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases”, Radiation research, Vol. 186/2, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR14445.1.
Yao, L. et al. (2010), “The role of RhoA/Rho kinase pathway in endothelial dysfunction”, Journal of Cardiovascular Disease Research, Vol. 1/4, Elsevier, Amsterdam, https://doi.org/10.4103/0975-3583.74258.