Exendin-4 restores glucolipotoxicity-induced gene expression in human coronary artery endothelial cells

Exendin-4, a stable GLP-1 receptor agonist, has been shown to stimulate insulin secretion. It has also been shown to exert beneficial effects on endothelial function that are independent of its glycemic effects. The molecular mechanisms underlying the protective actions of exendin-4 against diabetic glucolipotoxicity in endothelial cells largely remain elusive. We have investigated the long-term in vitro effect of palmitate or high glucose (simulating the diabetic milieu) and the role of exendin-4 on gene expression in human coronary artery endothelial cells. Gene expression profiling in combination with Western blotting revealed that exendin-4 regulates expression of a number of genes involved in angiogenesis, inflammation and thrombogenesis under glucolipotoxic conditions. Our results indicate that exendin-4 may improve endothelial cell function in diabetes through regulating expression of the genes, whose expression was disrupted by glucolipotoxicity. As endothelial dysfunction appears to be an early indicator of vascular damage, and predicts both progression of atherosclerosis and incidence of cardiovascular events, exendin-4 and possibly other incretin-based strategies may confer additional cardiovascular benefit beyond improved glycemic control.