Telmisartan attenuates hyperglycemia-exacerbated VCAM-1 expression and monocytes adhesion in TNFα-stimulated endothelial cells by inhibiting IKKβ expression

Vascul Pharmacol. 2016 Mar:78:43-52. doi: 10.1016/j.vph.2015.10.001. Epub 2015 Oct 8.

Abstract

Uncontrolled hyperglycemia accelerates endothelial damage and vascular inflammation caused by proinflammatory cytokines including tumor necrosis factor α (TNFα), which leads to arteriosclerotic cardiovascular diseases such as myocardial infarction. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is prescribed for treatment of hypertensive patients with concurrent diabetes mellitus (DM). Although a few clinical trials have suggested that telmisartan decreases cardiovascular complications in diabetic patients, the molecular mechanism for the beneficial effects remains elusive. Here, we investigated a molecular mechanism and effects of telmisartan on the expression of vascular cell adhesion molecule-1 (VCAM-1) and attachment of monocytes onto endothelial cells induced by TNFα in hyperglycemia-treated bovine aortic endothelial cells (BAEC). Telmisartan dose-dependently decreased hyperglycemia-aggravated IκB kinase β (IKKβ) expression and nuclear factor-κB (NF-κB) p65-Ser(536) phosphorylation, which accompanied a decrease in VCAM-1 expression and THP-1 monocytes adhesion. Among ARBs, including losartan and fimasartan, only telmisartan showed the inhibitory effects on expression of VCAM-1 and IKKβ, and phosphorylation of NF-κB p65-Ser(536). 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. Finally, ectopic expression of wild type (WT)-IKKβ significantly restored telmisartan-attenuated VCAM-1 expression, NF-κB p65-Ser(536) phosphorylation, and THP-1 monocytes adhesion. Taken together, our findings demonstrate that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by decreasing expression of IKKβ and VCAM-1 independently of PPARγ. Telmisartan may be useful for the treatment of DM-associated vascular inflammation and cardiovascular diseases.

Keywords: Fimasartan (PubChem CID: 9,870,652); Hyperglycemia; IKKβ; Losartan (PubChem CID: 3961); Telmisartan; Telmisartan (PubChem CID: 65,999); VCAM-1; Vascular inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Anilides / pharmacology
  • Animals
  • Benzimidazoles / pharmacology*
  • Benzoates / pharmacology*
  • Cattle
  • Cell Adhesion / drug effects
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / physiopathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Hyperglycemia / drug therapy*
  • Hyperglycemia / physiopathology
  • I-kappa B Kinase / genetics
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Monocytes / drug effects
  • PPAR gamma / metabolism
  • Rosiglitazone
  • Telmisartan
  • Thiazolidinediones / pharmacology
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • 2-chloro-5-nitrobenzanilide
  • Angiotensin II Type 1 Receptor Blockers
  • Anilides
  • Benzimidazoles
  • Benzoates
  • PPAR gamma
  • Thiazolidinediones
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Rosiglitazone
  • I-kappa B Kinase
  • Telmisartan