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

Background: 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. Aims: In this study, we observed the effects of telmisartan on monocrotaline (MCT)-induced Sprague Dawley (SD) rat model of PAH. Methods: After a single-dose injection of MCT (60 mg/kg), oral administration of telmisartan (10 mg/kg/d) was started from day I to day 28 or with saline as MCT control. The vasorelaxation and remodelling of pulmonary arteries; the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), Akt, eNOS; levels of phosphorylation of Ala (p-Akt) and phosphorylation of eNOS (p-eNOS) were analysed in isolated rat pulmonary arteries and cultured human pulmonary artery endothelial cells (HPAECs). Results: 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 PPAR gamma, 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 PPAR gamma or phosphoinositide 3-kinase (PI3K) signals transduction. In cultured HPAECs, treatment with telmisartan increased PPAR gamma expression and promoted the phosphorylation of Akt and eNOS, thereby increasing the production of NO. These effects were abolished by the inhibition of PPAR gamma or PI3K. Conclusion: Telmisartan protected against endothelial dysfunction in MCT-induced PAH through a PPAR gamma-dependent PI3K/Akt/eNOS pathway. Thus, telmisartan may be a promising therapeutic strategy for patients with a high risk of PAH. (C) 2013 Elsevier Ltd. All rights reserved.