Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3β-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 β (IKKβ) expression in endothelial cells. Because glycogen synthase 3β (GSK3β) is involved in inflammatory process by regulating nuclear factor-κB (NF-κB) activity, we investigated whether GSK3β mediates telmisartan-ameliorated vascular inflammation in hyperglycemia-treated endothelial cells and high-fat diet (HFD)-fed mice. Telmisartan remarkably induced GSK3β-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 GSK3β-S9A, a constitutively active mutant of GSK3β, significantly restored complete telmisartan-inhibited NF-κB p65-Ser⁵³⁶ phosphorylation, VCAM-1 expression, and THP-1 monocyte adhesion. In addition, it reversed telmisartan-repressed IKKβ expression. Among the ARB, including losartan and fimasartan, only telmisartan increased GSK3β-Ser⁹ phosphorylation, and telmisartan-induced GSK3β-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 IKKβ expression and downregulation of GSK3β-Ser⁹ phosphorylation. Taken together, our findings demonstrated that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by inducing GSK3β-Ser⁹ phosphorylation, which consequently inhibits IKKβ expression, NF-κB p65-Ser⁵³⁶ phosphorylation, and VCAM-1 expression in a PPARγ-independent manner.

Keywords: Fimasartan (PubChem CID: 9870652); GSK3β; Hyperglycemia; Losartan (PubChem CID: 3961); Telmisartan; Telmisartan (PubChem CID: 65999); VCAM-1; Vascular inflammation.