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.

Telmisartan ameliorates vascular endothelial dysfunction in coronary slow flow phenomenon (CSFP)

“…Ang II enhances the secretion of ET, reactive oxygen species, and inhibits the expression of NO eNOS in endothelial cells . Recent studies have confirmed that incubation with Ang II in vitro can directly induce endothelial dysfunction …”

“…Li et al demonstrated that TMST alleviated pulmonary artery endothelial dysfunction induced by monocrotaline through a PPARγ‐dependent phosphoinositide 3‐kinase/Akt/eNOS pathway. Hu et al has found that TMST improves Ang II endothelial dysfunction by activating HGF/Met system and PPARγ pathway. However, little information is available whether TMST can prevent endothelial dysfunction in CSFP.…”

“…The isometric contractile tension was measured according to a previous study . The thoracic aortic rings were vertically suspended in a jacketed organ bath containing 25‐mL Krebs solution that was continuously aerated with 95% O 2 and 5% CO 2 at 37°C.…”

“…Recently, Telmisartan (TMST), one of angiotensin‐receptor blocker, is a clinically available anti‐hypertensive medicine and has shown its potential properties for improving vascular endothelial function by selectively agitate peroxisome proliferation‐activated receptor (PPAR)γ . Hu et al has suggested that TMST could prevent endothelial dysfunction induced by angiotensin II in rabbit aorta by activating hepatocyte growth factor (HGF)/mesenchymal‐epithelial transition factor (Met) and PPARγ . However, it is unclear whether TMST protects vascular endothelial function in CSFP, as well as its other underling potential mechanisms.…”

Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II

“…In numerous respects, angiotensin II and natriuretic peptides may be considered physiological antagonists for each other, and the two peptide systems exert opposing effects on blood pressure and sodium conservation . At the level of the VSMC, ANP inhibits cell contraction and growth, while angiotensin II promotes them.…”