The roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes

Abstract

Vascular endothelial cell (VEC) dysfunction in diabetes has been associated with hyperglycaemia-induced intra- and extracellular glycation of proteins and to overproduction of glucose-derived free radicals. VEC protect their intracellular environment against an increased influx of glucose in face of hyperglycaemia by reducing the expression and plasma membrane abundance of their glucose transporter-1 (GLUT-1). We investigated the hypothesis that glucose-derived free radicals induce this down-regulatory mechanism in VEC, but proved the contrary. In fact, pro-oxidants significantly increased the expression and plasma membrane abundance of GLUT-1 and the rate of glucose transport in VEC while abolishing high-glucose-induced down-regulation of the hexose transport system. The resulting uncontrolled influx of glucose followed by overproduction of glucose-derived ROS further up-regulates the rate of glucose transport, and vice versa. This perpetuating glycoxidative stress finally leads to the collapse of the auto-regulatory protective mechanism and accelerates the development of dysfunctional endothelium in blood vessels.

Hyperthermia-induced Hsp90·eNOS Preserves Mitochondrial Respiration in Hyperglycemic Endothelial Cells by Down-regulating Glut-1 and Up-regulating G6PD Activity

“…7). ROS and oxidative stress are known to regulate Glut-1 (17,18), and NO is known to have anti-oxidant properties (40). Thus, by decreasing ROS the observed increase in NO produced by heat shock would lead to the observed decrease Glut-1 and glucose uptake (Fig.…”

“…Next we determined whether there is was any difference in glucose transporters in these cells. It has been previously established that Glut-1 and Glut-2 are the major glucose transporters found in BAECs (14,17,18,23). The Western blots of Glut-1 and Glut-2 showed that the Glut-1 is very much reduced in heat-shocked cells, whereas there was no change in Glut-2 (Fig.…”

“…Indeed, ROS has been proven to affect the regulation of glucose transport through Glut-1 and favor increased uptake of glucose by endothelial cells. Thus, alteration of oxidative stress in hyperglycemic endothelial cells was found to directly affect glucose homeostasis (17,18). Recently we demonstrated that non-lethal heat shock (hyperthermia) reduced superoxide generation (13).…”

“…Expression, stability, and function of Glut-1 are influenced by many factors, including glucose metabolites such as advanced glycation end product-induced oxidative stress and the ROS that is generated by enzymatic reactions such as NADPH oxidase and NOS (17)(18)(19). Indeed, ROS has been proven to affect the regulation of glucose transport through Glut-1 and favor increased uptake of glucose by endothelial cells.…”

Diabetes mellitus e alterações da glicemia em pacientes com desfecho desfavorável admitidos em unidade de terapia intensiva

“…Dois estudos adicionais avaliando desfecho em paciente com acidente vascular cerebral mostraram que hiperglicemia aguda e hiperglicemia de estresse prolongada estariam relacionadas a pior prognóstico e aumento da mortalidade, especialmente nos pacientes sem diagnóstico prévio de DM. 25,26 Umpierrez et al realizaram uma revisão com 2.030 pacientes e evidenciaram que a hiperglicemia hospitalar é um achado comum e representa um marcador de mau prognóstico e de mortalidade em pacientes com e sem história de DM. 17 Sechterberger et al realizaram um estudo com pacientes clínicos e cirúrgicos no qual constataram que glicemia média elevada e alta variabilidade dos níveis glicêmicos foram relacionadas à mortalidade na UTI em pacientes não diabéticos.…”