Telmisartan attenuates monocrotaline-induced pulmonary artery endothelial dysfunction through a PPAR gamma-dependent PI3K/Akt/eNOS pathway.

Pulmonary artery endothelial dysfunction has been demonstrated in pulmonary arterial hypertension (PAH). Telmisartan has beneficial effects in endothelial function in PAH patients; however, the underlying mechanisms for these effects remain unknown. In this study, we observed the effects of telmisartan on monocrotaline (MCT)-induced Sprague Dawley (SD) rat model of PAH. After a single-dose injection of MCT (60 mg/kg), oral administration of telmisartan (10 mg/kg/d) was started from day 1 to day 28 or with saline as MCT control. The vasorelaxation and remodelling of pulmonary arteries; the expression of peroxisome proliferator-activated receptor γ (PPARγ), Akt, eNOS; levels of phosphorylation of Akt (p-Akt) and phosphorylation of eNOS (p-eNOS) were analysed in isolated rat pulmonary arteries and cultured human pulmonary artery endothelial cells (HPAECs). Compared to MCT control group, telmisartan treatment ameliorated pulmonary artery endothelial dysfunction and remodelling, prevented the elevation of right ventricular systolic pressure (RVSP) induced by MCT. Immunoblotting results indicated lower levels of PPARγ, p-Akt and p-eNOS in pulmonary arteries treated with MCT alone and levels were significantly restored by co-treatment with telmisartan. In isolated pulmonary arteries, the impaired endothelium-dependent vasorelaxation of pulmonary arteries was improved following incubation with telmisartan for 12 h, whereas this effect was blocked by the inhibition of either PPARγ or phosphoinositide 3-kinase (PI3K) signals transduction. In cultured HPAECs, treatment with telmisartan increased PPARγ expression and promoted the phosphorylation of Akt and eNOS, thereby increasing the production of NO. These effects were abolished by the inhibition of PPARγ or PI3K. Telmisartan protected against endothelial dysfunction in MCT-induced PAH through a PPARγ-dependent PI3K/Akt/eNOS pathway. Thus, telmisartan may be a promising therapeutic strategy for patients with a high risk of PAH.

Li H ，Lu W ，Cai WW ，Wang PJ ，Zhang N ，Yu CP ，Wang DL ，Liu BC ，Sun W ... -  《-》

Nicorandil attenuates monocrotaline-induced vascular endothelial damage and pulmonary arterial hypertension.

Sahara M ，Sata M ，Morita T ，Hirata Y ，Nagai R ... -  《PLoS One》

Administration of telmisartan reduced systolic blood pressure and oxidative stress probably through the activation of PI3K/Akt/eNOS pathway and NO release in spontaneously hypertensive rats.

Xu L ，Liu Y 《-》

Genistein attenuates monocrotaline-induced pulmonary arterial hypertension in rats by activating PI3K/Akt/eNOS signaling.

Zheng Z ，Yu S ，Zhang W ，Peng Y ，Pu M ，Kang T ，Zeng J ，Yu Y ，Li G ... -  《-》

Telmisartan inhibits vasoconstriction via PPARγ-dependent expression and activation of endothelial nitric oxide synthase.

Yuen CY ，Wong WT ，Tian XY ，Wong SL ，Lau CW ，Yu J ，Tomlinson B ，Yao X ，Huang Y ... -  《-》