title: Telmisartan prevents angiotensin II-induced endothelial dysfunction in rabbit aorta via activating HGF/Met system and PPARγ pathway.
abstract: Telmisartan with partial activation of peroxisome proliferator-activated receptor γ (PPARγ) powerfully reduces blood pressure, improves endothelial function and lipid metabolism. Hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/Met) system in the local vasculature plays a pivotal role in maintaining normal endothelial function. This study is aimed to evaluate whether telmisartan directly prevents angiotensin II (Ang II)-induced endothelial dysfunction (ED) via activating HGF/Met system and/or PPARγ pathway. The isolated aortic rings of rabbits were incubated with Ang II (0.01-1 μM), telmisartan (0.1-10 μM), SU11274 (5 μM) as a specific Met inhibitor, GW9662 (10 μM) as a PPARγ antagonist alone or a combination for 6 h. Ang II obviously inhibited the mRNA and protein expression of HGF, Met and PPARγ, and the accumulative concentration-relaxation of the aortic rings to acetylcholine, among which the inhibitory effect of 1 μM Ang II was most significant. By contrast, telmisartan significantly increased the mRNA and protein expression of HGF, Met, and PPARγ, thus preventing Ang II-induced ED in a dose-dependent pattern. However, SU11274, GW9662 or a combination of both partially abolished the protective effects derived from telmisartan, with the effect of SU11274 exceeding that of GW9662. These results demonstrate that Ang II-induced ED in rabbit aortic rings in vitro can be prevented by telmisartan through selective PPARγ-modulating pathway. Moreover, this study indicates for the first time that activating HGF/Met system in the local vasculature is involved in the protective mechanism of telmisartan.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Anhui Medical University, 218 Jixi Road, Hefei, Anhui Province, 230022, China.
authors.forename: Ze-Ping
authors.initials: ZP
authors.lastname: Hu
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Fang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.forename: Nan
authors.initials: N
authors.lastname: Fang
authors.forename: Bang-Ning
authors.initials: BN
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011817:Rabbits; D012697:Serine Endopeptidases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077333:Telmisartan
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D007211:Indoles; D047495:PPAR gamma; D010879:Piperazines; D013449:Sulfonamides; C081092:HGF activator; D012697:Serine Endopeptidases; D000077333:Telmisartan
keywords: aortic ring; endothelial function; hepatocyte growth factor; peroxisome proliferator-activated receptor γ; telmisartan