title: Telmisartan attenuates monocrotaline-induced pulmonary artery endothelial dysfunction through a PPAR gamma-dependent PI3K/Akt/eNOS pathway.
abstract: 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.
  
  
  OBJECTIVE
  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 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).
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Cai
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Chengdu Medical College, Chengdu 610500, China.
authors.forename: Pei-Jian
authors.initials: PJ
authors.lastname: Wang
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Yu
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China. Electronic address: wangdongliang202@yahoo.com.cn.
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Wang
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: Liu
authors.affiliation: Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077333:Telmisartan
keywords: Endothelium dysfunction; Peroxisome proliferator-activated receptor γ; Phosphoinositide 3-kinase; Pulmonary arterial hypertension; Telmisartan