A natural protective mechanism against hyperglycaemia in vascular endothelial and smooth-muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid

Abstract

Bovine aortic endothelial and smooth-muscle cells down-regulate the rate of glucose transport in the face of hyperglycaemia, thus providing protection against deleterious effects of increased intracellular glucose levels. When exposed to high glucose concentrations these cells reduced the mRNA and protein content of their typical glucose transporter, GLUT-1, as well as its plasma-membrane abundance. Inhibition of the lipoxygenase (LO) pathway, and particularly 12-LO, reversed this glucose-induced down-regulatory process and restored the rate of hexose transport to the level seen in vascular cells exposed to normal glucose levels. This reversal was accompanied by increased levels of GLUT-1 mRNA and protein, as well as of its plasma-membrane content. Exposure of the vascular cells to elevated glucose concentrations increased by 2–3-fold the levels of cell-associated and secreted 12-hydroxyeicosatetraenoic acid (12-HETE), the product of 12-LO. Inhibition of 15- and 5-LO, cyclo-oxygenases 1 and 2, and eicosanoid-producing cytochrome P450 did not modify the hexose-transport system in vascular cells. These results suggest a role for HETEs in the autoregulation of hexose transport in vascular cells. 8-Iso prostaglandin F2α, a non-enzymic oxidation product of arachidonic acid, had no effect on the hexose-transport system in vascular cells exposed to hyperglycaemic conditions. Taken together, these findings show that hyperglycaemia increases the production rate of 12-HETE, which in turn mediates the down-regulation of GLUT-1 expression and the glucose-transport system in vascular endothelial and smooth-muscle cells.

Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?

“…Reducing GLUT-2 expression may therefore be beneficial in diabetes. Chronic exposure of endothelial cells to high glucose will has also been shown to reduce GLUT-1 expression, and a 36-h exposure of BAECs and smooth-muscle cells to 23 mmol/L glucose led to a down-regulation of the rate of glucose transport as well as GLUT-1 mRNA and protein (Alpert et al 2002). The same group, however, failed to show changes in BAECs after a 24-h exposure to high glucose (Kaiser et al 1993).…”

Eicosanoids and renal vascular function in diseases

“…Diabetic db/db mice have increased endothelial cell 12/15-LOX and increased binding of monocytes [143]. 12/15-LOX expression is also markedly increased in obese Zucker rats and is associated with vascular inflammation [144,145]. Interestingly, 12/15-LOX is one of a few genes that are increased in the pancreatic β-cell of the insulin-resistant prediabetic Zucker diabetic fatty rat [145].…”

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…This substrate regulation protects the cells against the detrimental consequences of increased glucose influx (e.g., autoxidation, protein glycation, mitochondria uncoupling, etc.) (Alpert et al, 2002(Alpert et al, , 2005Greco-Perotto et al, 1992;Kaiser et al, 1993;Kaufman et al, 2015;Sasson and Cerasi, 1986;Sasson et al, 1987;Totary-Jain et al, 2005). Plausibly, such protective mechanisms are less efficient in susceptible individuals or their Weir and Bonner-Weir (2004) and Kuritzky and Samraj (2011) and depicts the adaptive phase, where augmented insulin secretion compensates for the peripheral insulin resistance and maintains blood glucose level below the hyperglycemic threshold, and the second decomposition phase, where beta cell function deteriorates and insulin levels decline, leading to hyperglycemia and overt diabetes.…”