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. 2021 Oct 26;13(11):3793.
doi: 10.3390/nu13113793.

The Role of 20-HETE, COX, Thromboxane Receptors, and Blood Plasma Antioxidant Status in Vascular Relaxation of Copper-Nanoparticle-Fed WKY Rats

Michał Majewski  1 , Jerzy Juśkiewicz  2 , Magdalena Krajewska-Włodarczyk  3 , Leszek Gromadziński  4 , Katarzyna Socha  5 , Ewelina Cholewińska  6 , Katarzyna Ognik  6
Affiliations

The Role of 20-HETE, COX, Thromboxane Receptors, and Blood Plasma Antioxidant Status in Vascular Relaxation of Copper-Nanoparticle-Fed WKY Rats

Michał Majewski et al. Nutrients. .

Abstract

Recently, the addition of copper nanoparticles (NPs) in a daily diet (6.5 mg/kg) was studied in different animal models as a possible alternative to ionic forms. Male Wistar-Kyoto rats (24-week-old, n = 11) were fed with copper, either in the form of carbonate salt (Cu6.5) or metal-based copper NPs (NP6.5), for 8 weeks. The third group was fed with a half dose of each (NP3.25 + Cu3.25). The thoracic aorta and blood plasma was studied. Supplementation with NP6.5 decreased the Cu (×0.7), Cu/Zn-ratio (×0.6) and catalase (CAT, ×0.7), and increased Zn (×1.2) and superoxide dismutase (SOD, ×1.4). Meanwhile, NP3.25 + Cu3.25 decreased the Cu/Zn-ratio (×0.7), and CAT (×0.7), and increased the daily feed intake (×1.06). Preincubation with either the selective cyclooxygenase (COX)-2 inhibitor, or the non-selective COX-1/2 inhibitor attenuated vasodilation of rat thoracic aorta in the NP6.5 group exclusively. However, an increased vasodilator response was observed in the NP6.5 and NP3.25 + Cu3.25 group of rats after preincubation with an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and the thromboxane receptor (TP) antagonist. Significant differences were observed between the NP6.5 and NP3.25 + Cu3.25 groups of rats in: dietary intake, acetylcholine-induced vasodilation, and response to COX-inhibitors. Copper NPs in a standard daily dose had more significant effects on the mechanism(s) responsible for the utilization of reactive oxygen species in the blood plasma with the participation of prostanoids derived from COX-2 in the vascular relaxation. Dietary copper NPs in both doses modified vasodilation through the vasoconstrictor 20-HETE and the TP receptors.

Keywords: 20-HETE; HET0016; NS-398; SQ-29,548; aging; furegrelate; indomethacin; thromboxane-A2.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The influence of experimental diets on rat body weight (A–C), and daily feed intake (D). Values are expressed as means ± SD of n = 11 rats (A–C), and of m = 56 days of supplementation (D). NP3.25 + Cu3.25 increased by 1.06-fold the daily feed intake.
Figure 2
Figure 2
The influence of experimental diets on Cu, Zn content (A–C), and antioxidant mechanism (D–H) in blood plasma. Values are expressed as means ± SD of n = 11 rats. Supplementation with NP6.5 decreased the Cu (×0.7), Cu/Zn-ratio (×0.6), catalase (CAT, ×0.7), and increased Zn (×1.2), and superoxide dismutase (SOD, ×1.4). NP3.25 + Cu3.25 decreased the Cu/Zn-ratio (×0.7), and CAT (×0.7).
Figure 3
Figure 3
The relaxant response to acetylcholine in the isolated thoracic rings from rats supplemented with Cu6.5, NP3.25 + Cu3.25, and NP6.5. Results are means ± SEM, * compared to Cu6.5, # compared to NP3.25 + Cu3.25, p < 0.05 of n = 11 rats; ANOVA/Tukey’s. The red curve is the nonlinear regression model (log agonist vs. response). A significant change in the relaxant response was observed between the NP3.25 + Cu3.25 and NP6.5 groups of rats.
Figure 4
Figure 4
The influence of 1400 W on the relaxant response to acetylcholine. Aortic rings from rats supplemented with Cu6.5 (A), NP3.25 + Cu3.25 (B), and NP6.5 (C) were pre-incubated with the inducible nitric oxide synthase inhibitor (1400 W, 30 min, 1 μM). Results are means ± SEM, p > 0.05 of n = 5 rats; two-way ANOVA/Sidak’s. Preincubation with the selective iNOS inhibitor did not modify the vasodilation.
Figure 5
Figure 5
The influence of NS-398 and indomethacin (Indo) on the relaxant response to acetylcholine. Aortic rings from rats supplemented with Cu6.5 (A), NP3.25 + Cu3.25 (B), and NP6.5 (C) were pre-incubated with the selective cyclooxygenase-2 (COX-2) inhibitor (NS-398, 30 min, 10 μM) and the non-selective COX-1/2 inhibitor (Indo, 30 min, 10 μM). Results are means ± SEM, * p < 0.05 of n = 5 rats; ANOVA/Tukey’s. Preincubation with NS-398 and indomethacin attenuated vasodilation of rat thoracic aorta in the NP6.5 group exclusively.
Figure 6
Figure 6
The influence of HET0016 on the relaxant response to acetylcholine. Aortic rings from rats supplemented with Cu6.5 (A), NP3.25 + Cu3.25 (B), and NP6.5 (C) were pre-incubated with an inhibitor of 20-HETE formation (HET0016, 30 min, 0.1 μM). Results are the means ± SEM, * p < 0.05 two-way ANOVA/Sidak’s. Number of animals is indicated in parenthesis. Preincubation with HET0016 potentiated vasodilation in NP3.25 + Cu3.25, and NP6.5 fed rats. This was not observed in the control group (Cu6.5).
Figure 7
Figure 7
The influence of furegrelate and SQ-29,548 on the relaxant response to acetylcholine. Aortic rings from rats supplemented with Cu6.5 (A), NP3.25 + Cu3.25 (B), and NP6.5 (C) were pre-incubated with the thromboxane-A2 synthetase inhibitor (FURE, 30 min, 1 μM) and the thromboxane-A2 receptor antagonist (SQ-29,548, 30 min, 1 μM). Results are means ± SEM, * p < 0.05; ANOVA/Tukey’s. Number of animals is indicated in parenthesis. SQ-29,548 potentiated vasodilation in the NP3.25 + Cu3.25 and in the NP6.5 group of rats.
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