Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3ß-Ser9 phosphorylation in endothelial cells and mouse aortas.

ABSTRACT

Telmisartan, an angiotensin II type 1 receptor blocker (ARB), attenuates hyperglycemia-aggravated vascular inflammation by decreasing IκB kinase ß (IKKß) expression in endothelial cells. Because glycogen synthase 3ß (GSK3ß) is involved in inflammatory process by regulating nuclear factor-κB (NF-κB) activity, we investigated whether GSK3ß mediates telmisartan-ameliorated vascular inflammation in hyperglycemia-treated endothelial cells and high-fat diet (HFD)-fed mice. Telmisartan remarkably induced GSK3ß-Ser9 phosphorylation in hyperglycemia-treated endothelial cells that accompanied a decrease in hyperglycemia-induced NF-κB p65-Ser536 phosphorylation, vascular cell adhesion molecule-1 (VCAM-1) expression, and THP-1 monocyte adhesion. Ectopic expression of GSK3ß-S9A, a constitutively active mutant of GSK3ß, significantly restored complete telmisartan-inhibited NF-κB p65-Ser536 phosphorylation, VCAM-1 expression, and THP-1 monocyte adhesion. In addition, it reversed telmisartan-repressed IKKß expression. Among the ARB, including losartan and fimasartan, only telmisartan increased GSK3ß-Ser9 phosphorylation, and telmisartan-induced GSK3ß-Ser9 phosphorylation remained unchanged by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Finally, in the aortas of HFD-fed mice, telmisartan treatment significantly attenuated HFD-induced upregulation of NF-κB p65-Ser536 phosphorylation, VCAM-1 expression, and IKKß expression and downregulation of GSK3ß-Ser9 phosphorylation. Taken together, our findings demonstrated that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by inducing GSK3ß-Ser9 phosphorylation, which consequently inhibits IKKß expression, NF-κB p65-Ser536 phosphorylation, and VCAM-1 expression in a PPARγ-independent manner.