Avaliação dos efeitos cardiometabólicos do inibidor de integrase Dolutegravir

Abstract

Increasing evidence demonstrates the increased rates of cardiovascular disease among people living with HIV / AIDS. Both HIV-1 infection and antiretroviral therapy are implicated in the development of dyslipidemia, increased oxidative stress and endothelial dysfunction, these being important pathophysiological events for the development of atherosclerosis. Dolutegravir (DTG) is an inhibitor of the HIV-1 integrase enzyme that has been used as the first antiretroviral therapy option since 2017. However, there is no consistent data in the literature demonstrating the cardiovascular and metabolic actions of integrase inhibitors, particularly of the DTG. The objective of this work was to evaluate the impact of subchronic treatment with DTG on the cardiovascular system, lipid profile, liver function and oxidative stress in C57Bl / 6J mice. Male mice were treated with DTG (10mg / kg) or vehicle for 28 days, via gavage. Concentration-response curves with acetylcholine and phenylephrine were performed on aortic rings, using an organ bath system. Treatment with DTG generated a reduction in the relaxing response induced by acetylcholine. This effect was associated with a lower production of NO in the aortas, corroborated by the reduction in the expression of eNOS and nNOS also observed in this site. Although no difference was found in the production of superoxide and hydrogen peroxide, there was an increase in the formation of nitrotyrosine, suggesting greater production of peroxynitrite in the aortas of the DTG group. There were no changes in blood glucose and serum lipid profile. However, there was an increase in serum TGP transaminase and hepatic lipid peroxidation, in addition to a decrease in SOD activity in the liver. Such effects were associated with the development of fatty liver in the DTG group. Cardiac histopathology, blood pressure and electrocardiographic assessment showed no difference between groups. The results of this work allow us to conclude that the subchronic treatment with DTG induced endothelial dysfunction, mediated by the decrease in the bioavailability of NO, due to the lower expression of NOS. Although no changes were observed in the cardiac parameters evaluated, the DTG induced steatosis and increased hepatic oxidative stress.