Copper exposure at a daily dose twice the recommended in diabetic rats induces oxidative stress, vascular dysfunction and perivascular adipose tissue inflammation in diabetic rats

Abstract

Individuals with diabetes often have a heightened risk of cardiovascular diseases and present copper (Cu) metabolism imbalances. We investigated the effect of chronic exposure to twice the recommended daily dose of CuCl₂ on vascular reactivity in isolated thoracic aorta segments of diabetic and non-diabetic rats. Eighty male Wistar rats, aged 12 weeks, were divided into four groups: Control (Ct), Copper (Cu), Diabetes Mellitus (DM), and Diabetes + Copper (DM+Cu). Type 1 diabetes was induced using a single dose of streptozotocin (65 mg/kg i.p), and the animals exposed to Cu received twice the recommended daily dose (25.7 µg/Kg/day CuCl₂) for 30 days. After treatment, we investigated vascular reactivity and performed histological evaluations on samples of aortas and perivascular adipose tissue (PVAT). Our findings revealed pronounced weight loss and higher hyperglycemia in the DM+Cu group compared to DM, along with increased pro-inflammatory factors in PVAT (IL-6). Vascular reactivity to phenylephrine decreased without PVAT, accompanied by elevated vasodilator factors: NO and H₂O₂, and involvement of K+ channels. Additionally, we observed an increase in the thickness of the aorta wall, collagen deposition. In the presence of PVAT, vascular reactivity increased in the DM+Cu and Cu groups. These findings demonstrate that exposure to double the recommended Cu dose in diabetic animals leads to endothelial and PVAT dysfunction, associated with elevation of vasodilator and pro-inflammatory factors.