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

Autor: He Li, Dong-Liang Wang, Ning Zhang, Pei-Jian Wang, Wei Sun, Wei-Wei Cai, Chang-Ping Yu, Bai-Cheng Liu, Wei Lu
Rok vydání: 2013
Předmět:
Pulmonary and Respiratory Medicine
Male
medicine.medical_specialty
Nitric Oxide Synthase Type III
Hypertension
Pulmonary
Peroxisome proliferator-activated receptor
Pulmonary Artery
Benzoates
Rats
Sprague-Dawley
Phosphatidylinositol 3-Kinases
Enos
Internal medicine
medicine.artery
medicine
Animals
Pharmacology (medical)
Telmisartan
Endothelial dysfunction
Phosphorylation
Protein kinase B
PI3K/AKT/mTOR pathway
chemistry.chemical_classification
Phosphoinositide 3-kinase
Monocrotaline
biology
business.industry
Biochemistry (medical)
medicine.disease
biology.organism_classification
Rats
PPAR gamma
Disease Models
Animal
Endocrinology
chemistry
Pulmonary artery
biology.protein
Benzimidazoles
Endothelium
Vascular
business
Angiotensin II Type 1 Receptor Blockers
Proto-Oncogene Proteins c-akt
medicine.drug
Signal Transduction
Zdroj: Pulmonary pharmacologytherapeutics. 28(1)
ISSN: 1522-9629
Popis: 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 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. Conclusion 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.
Databáze: OpenAIRE
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