Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3β-Ser{sup 9} phosphorylation in endothelial cells and mouse aortas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, 120-1, Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul 05030 (Korea, Republic of)
- Department of Pharmacology, School of Medicine, Eulji University, 77 Gyeryong-ro, 771 Beon-gil, Jung-gu, Daejeon 34824 (Korea, Republic of)
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25 Bongjung-ro, Cheonan, Chungcheongnam do 31151 (Korea, Republic of)
- Department of Molecular Medicine, Ewha Womans University Medical School, 1071, Anyangcheon-ro, Yangcheon-gu, Seoul 07985 (Korea, Republic of)
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-Ser{sup 9} phosphorylation in hyperglycemia-treated endothelial cells that accompanied a decrease in hyperglycemia-induced NF-κB p65-Ser{sup 536} 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-Ser{sup 536} 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-Ser{sup 9} phosphorylation, and telmisartan-induced GSK3β-Ser{sup 9} 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-Ser{sup 536} phosphorylation, VCAM-1 expression, and IKKβ expression and downregulation of GSK3β-Ser{sup 9} phosphorylation. Taken together, our findings demonstrated that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by inducing GSK3β-Ser{sup 9} phosphorylation, which consequently inhibits IKKβ expression, NF-κB p65-Ser{sup 536} phosphorylation, and VCAM-1 expression in a PPARγ-independent manner. - Highlights: • Telmisartan inhibits GSK3β activity by inducing GSK3β-Ser{sup 9} phosphorylation. • Increased GSK3β-Ser{sup 9} phosphorylation leads to a decrease in IKKβ expression. • Reduced IKKβ expression attenuates NF-κB p65 phosphorylation and VCAM-1 expression. • Finally, these mediate ameliorating effects of telmisartan on vascular inflammation.
- OSTI ID:
- 22719092
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 491, Issue 4; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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