The Effect of an Elevated Dietary Copper Level on the Vascular Contractility and Oxidative Stress in Middle-Aged Rats

Abstract

Copper (Cu), being an essential mineral, plays a crucial role in maintaining physiological homeostasis across multiple bodily systems, notably the cardiovascular system. However, an increased Cu level in the body may cause blood vessel dysfunction and oxidative stress, which is unfavorable for the cardiovascular system. Middle-aged (7–8 months old) male Wistar rats (n/group = 12) received a diet supplemented with 6.45 mg Cu/kg (100% of the recommended daily dietary quantity of copper) for 8 weeks (Group A). The experimental group received 12.9 mg Cu/kg of diet (200%—Group B). An ex vivo study revealed that supplementation with 200% Cu decreased the contraction of isolated aortic rings to noradrenaline (0.7-fold) through FP receptor modulation. Vasodilation to sodium nitroprusside (1.10-fold) and acetylcholine (1.13-fold) was potentiated due to the increased net effect of prostacyclin derived from cyclooxygenase-1. Nitric oxide (NO, 2.08-fold), superoxide anion (O2•−, 1.5-fold), and hydrogen peroxide (H2O2, 2.33-fold) measured in the aortic rings increased. Blood serum antioxidant status (TAS, 1.6-fold), Cu (1.2-fold), Zn (1.1-fold), and the Cu/Zn ratio (1.4-fold) increased. An increase in Cu (1.12-fold) and the Cu/Zn ratio (1.09-fold) was also seen in the rats’ livers. Meanwhile, cyclooxygenase-1 (0.7-fold), cyclooxygenase-2 (0.4-fold) and glyceraldehyde 3-phosphate dehydrogenase (0.5-fold) decreased. Moreover, a negative correlation between Cu and Zn was found (r = −0.80) in rat serum. Supplementation with 200% Cu did not modify the isolated heart functioning. No significant difference was found in the body weight, fat/lean body ratio, and organ weight for either the heart or liver, spleen, kidney, and brain. Neither Fe nor Se, the Cu/Se ratio, the Se/Zn ratio (in serum and liver), heme oxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), or intercellular adhesion molecule-1 (iCAM-1) (in serum) were modified. Supplementation with 200% of Cu potentiated pro-oxidant status and modified vascular contractility in middle-aged rats.

Copper Supplementation in Young Wistar Rats

“…In addition, there were no differences in the weights of the brain, heart, kidney, liver, or spleen. Previous studies support the data presented in this article [11]. Consistent with our research, Filetti et al (2023) reported that there were no significant differences in weight between the control group and the groups that were administered different amounts of copper [17].…”

“…Compared with that in the control group, the vasodilatory response to acetylcholine in the experimental group tended to potentiate vasodilation. It is worth mentioning to the increase in vasodilation in aged rats that was previously observed [11]. Both selective COX-2 inhibition and nonselective COX inhibition (simultaneous COX-1 and COX-2 inhibition) attenuated the vasodilator net effect of prostanoids on acetylcholine-induced vascular relaxation, indicating the decreased participation of vasodilator prostanoids derived from COX-2 in vascular tone regulation.…”

“…Through our previous experimental findings, we discovered that increased copper intake in middleaged rats led to reduced vasoconstriction when exposed to noradrenaline. Additionally, preincubation with a PGF2α analog (which is a selective FP receptor antagonist) rendered the vasoconstrictor response insignificant across the groups, suggesting that FP receptors are involved in reduced contraction in copper-supplemented middle-aged rats [11]. In the present study, this was not the case, and surprisingly, a selective iNOS inhibitor potentiated vascular contraction in response to noradrenaline, indicating that increased production of NO derived from iNOS constitutes a compensatory mechanism in copper-supplemented rats.…”

“…There are multiple biomarkers and methods of measurement available to assess antioxidant status. Recent studies have utilized total antioxidant status (TAS) [15], and we also used this method previously to discover increased TAS in aged rats [11]. However, in the present study, neither the TAS nor the MDA, SOD or CAT levels in the blood, arteries, or heart of the rats were altered.…”

“…Over the past few years, numerous studies have indicated that a group of GAPDH molecules move to the nucleus in response to various stressors, many of which are linked to oxidative stress [13]. Unlike young rats, our previous research showed that middle-aged rats experienced a decrease in the levels of COX-1, COX-2, and GAPDH in their blood serum when they were given a greater amount of dietary copper (200%) [11].…”