Endocrine Abstracts

Uncontrolled hyperglycemia accelerates endothelial damage and vascular inflammation caused by proinflammatory cytokines including tumor necrosis factor α (TNFα), which leads to arteriosclerotic cardiovascular diseases. Glycogen synthase kinase 3β (GSK3β) is reported to mediate TNFα-stimulated nuclear factor-κB (NF-κB) activation and expression of vascular adhesion molecules. Although a few clinical trials have suggested that telmisartan, an angiotensin II type 1 receptor blocker (ARB), decreases cardiovascular complications in diabetic patients, the underlying molecular mechanisms for the beneficial effects have not been fully elucidated. Here, we investigated a molecular mechanism mediating the telmisartan’s beneficial effects on vascular inflammation in hyperglycemia-treated endothelial cells. Telmisartan dose-dependently attenuated the hyperglycemia-aggravated vascular cell adhesion molecule-1 (VCAM-1) expression and THP-1 monocytes adhesion, which accompanied an increased GSK3β-Ser⁹ phosphorylation and a decreased NF-κB p65-Ser⁵³⁶ phosphorylation. Among ARBs, including losartan and fimasartan, only telmisartan induced GSK3β-Ser⁹ phosphorylation and showed the inhibitory effects on expression of VCAM-1 and phosphorylation of NF-κB p65-Ser⁵³⁶. The telmisartan’s beneficial effects were not changed by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, although GW9662 clearly inhibited rosiglitazone-induced CD36 expression. Ectopic expression of GSK3β-S9A, a constitutively active mutant of GSK3β, significantly restored the telmisartan-attenuated VCAM-1 expression, NF-κB p65-Ser⁵³⁶ phosphorylation, and THP-1 monocytes adhesion. Finally, both increased NF-κB p65-Ser⁵³⁶ phosphorylation and decreased GSK3β-Ser⁹ phosphorylation in the aortas from high-fat fed mice were reversed by treating with telmisartan. Taken together, our findings demonstrate that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation at least in part by increasing GSK3β-Ser⁹ phosphorylation, which mediates a decreased VCAM-1 expression in a PPARγ-independent manner. Telmisartan may be useful for the treatment of DM-associated vascular inflammation and cardiovascular diseases.