title: Telmisartan attenuates hyperglycemia-exacerbated VCAM-1 expression and monocytes adhesion in TNFα-stimulated endothelial cells by inhibiting IKKβ expression.
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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, 120-1, Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul 143-729, Korea.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Song
authors.affiliation: Department of Molecular Medicine, Ewha Womans University Medical School, 911-1, Mok-6-dong, Yangcheon-gu, Seoul 158-710, Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine, Ewha Womans University Medical School, 911-1, Mok-6-dong, Yangcheon-gu, Seoul 158-710, Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Ulsan College of Medicine, 388-1 Pungnap2-dong, Songpa-gu, Seoul 138-736, Korea.
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.affiliation: Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, and Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Pharmacology, School of Medicine, Eulji University, 77 Gyeryong-ro 771 Beon-gil, Jung-gu, Daejeon 301-746, Korea.
authors.forename: Soon Ae
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Eulji University, 77 Gyeryong-ro 771 Beon-gil, Jung-gu, Daejeon 301-746, Korea. Electronic address: biohyong@hanmail.net.
authors.forename: Du-Hyong
authors.initials: DH
authors.lastname: Cho
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D009000:Monocytes / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D000077333:Telmisartan; D045162:Thiazolidinediones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000077154:Rosiglitazone; D051550:I-kappa B Kinase; D000077333:Telmisartan
keywords: Fimasartan (PubChem CID: 9,870,652); Hyperglycemia; IKKβ; Losartan (PubChem CID: 3961); Telmisartan; Telmisartan (PubChem CID: 65,999); VCAM-1; Vascular inflammation