Nombre: MÔNICA GOLDNER
Fecha de publicación: 01/04/2025
Junta de examinadores:
Nombre |
Papel |
|---|---|
| BIANCA PRANDI CAMPAGNARO | Examinador Externo |
| ROGER LYRIO DOS SANTOS | Examinador Interno |
Sumario: Iron is an essential trace element for the human body, but its excess is toxic, causing
several damages, including to the cardiovascular system. Studies show that an excess
of this metal causes vasculopathy characterized by remodeling, vasoconstrictor
hyperreactivity, atherosclerosis, and oxidative stress in vascular tissue. In addition, the
arachidonic acid/cyclooxygenase (AA-COX) pathway, which is heavily involved in
inflammation, oxidative stress, and endothelial dysfunction in various conditions, has
not yet been investigated in the vasculopathy associated with iron overload. Thus, this
study aimed to determine whether the cyclooxygenase (COX) pathway is involved in
vascular dysfunction induced by chronic iron overload in rats. For this purpose, male
Wistar rats (~200 g) were divided into two groups: control (Ct) and iron (Fe). Iron was
administered i.p. injections (100 mg/kg/day, 5 times per week for 4 weeks), while the
Ct group received 0.9 % NaCl following the same treatment regimen. After 4 weeks,
blood pressure was measured, and the animals were then euthanized under general
anesthesia. Blood was collected for iron and C-reactive protein analysis, the tibia for
bone growth assessment, and the thoracic aorta and the 3rd branch of the superior
mesenteric artery for in vitro vascular reactivity studies. Additionally, another segment
of the aorta was collected for prostanoid release analysis and its metabolites, electron
microscopy, gene expression, and inflammatory cytokine quantification. Data were
analyzed using an unpaired Student's t-test, two-way ANOVA, and Bonferroni post-
hoc test, with significance set at P<0.05. Rats in the Fe group showed an increase in
serum ferritin levels, while blood pressure, heart rate, and C-reactive protein levels
remained similar to those in the Ct group. The Fe group exhibited increased vascular
responsiveness to phenylephrine in the aorta, which was blocked by the COX inhibitor
indomethacin (10 M). The EP1 receptor antagonist SC-19220 (10 M) and the
selective COX-2 inhibitor NS-398 (1 M) also reduced the contractile response
exclusively in the Fe group, whereas the TP receptor antagonist SQ-29548 (1 M) had
no effect. The IP receptor antagonist CAY-10441 (100 nM) increased the contractile
response only in the Ct group, with no effect in the Fe group. The reactivity of the
mesenteric resistance artery was similar between groups, and indomethacin, NS-398,
and SQ-29548 attenuated the contractile response in both. SC-19220 and CAY-10441
had no effect. In the aorta of the Fe group, there was a disruption in endothelial cell
confluence associated with greater iron deposition. Furthermore, an increase in
prostaglandin I2 release was observed, with no change in PGE2 levels, along with
enhanced macrophage activity and increased gene expression of M1 activation
markers (CD86) in the aorta of iron-overloaded animals. Thus, the AA-COX pathway
appears to contribute to the vasoconstrictor hyperreactivity of the aorta in iron
overload, with increased COX-2 activity, EP1 receptor activation, and impaired IP
modulation. These changes were associated with signs of inflammation, including
greater macrophage activation and structural damage to the aortic endothelium.
