Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3 beta-Ser(9) phosphorylation in endothelial cells and mouse aortas

초록

Telmisartan, an angiotensin II type 1 receptor blocker (ARB), attenuates hyperglycemia-aggravated vascular inflammation by decreasing IKB kinase beta (IKK beta) expression in endothelial cells. Because glycogen synthase 3 beta (GSK3 beta) is involved in inflammatory process by regulating nuclear factor-KB (NF-kappa B) activity, we investigated whether GSK3 beta mediates telmisartan-ameliorated vascular inflammation in hyperglycemia-treated endothelial cells and high-fat diet (HFD)-fed mice. Telmisartan remarkably induced GSK3 beta-Ser(9) phosphorylation in hyperglycemia-treated endothelial cells that accompanied a decrease in hyperglycemia-induced NF-KB p65-Ser(536) phosphorylation, vascular cell adhesion molecule 1 (VCAM-1) expression, and THP-1 monocyte adhesion. Ectopic expression of GSK3 beta-S9A, a constitutively active mutant of GSK3 beta, significantly restored complete telmisartan-inhibited NF-KB p65-Ser(536) phosphorylation, VCAM-1 expression, and THP-1 monocyte adhesion. In addition, it reversed telmisartan-repressed IKK beta expression. Among the ARB, including losartan and fimasartan, only telmisartan increased GSK3 beta-Ser(9) phosphorylation, and telmisartan-induced GSK3 beta-Ser(9) phosphorylation remained unchanged by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonist. Finally, in the aortas of HFD-fed mice, telmisartan treatment significantly attenuated HFD-induced upregulation of NF-KB p65-Ser(536) phosphorylation, VCAM-1 expression, and IKK beta expression and downregulation of GSK3 beta-Ser(9) phosphorylation. Taken together, our findings demonstrated that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by inducing GSK3 beta-Ser(9) phosphorylation, which consequently inhibits IKK beta expression, NF-KB p65-Ser(536) phosphorylation, and VCAM-1 expression in a PPAR gamma-independent manner. (C) 2017 Elsevier Inc. All rights reserved.

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