替米沙坦通过 PPARγ 依赖的 PI3K/Akt/eNOS 通路减轻野百合碱诱导的肺动脉内皮功能障碍。
Telmisartan attenuates monocrotaline-induced pulmonary artery endothelial dysfunction through a PPAR gamma-dependent PI3K/Akt/eNOS pathway.
机构信息
Department of Respiratory Disease, The 202th Hospital of PLA, Shenyang 110812, China.
Department of Cardiology, The First Affiliated Hospital, Chengdu Medical College, Chengdu 610500, China.
出版信息
Pulm Pharmacol Ther. 2014 Jun;28(1):17-24. doi: 10.1016/j.pupt.2013.11.003. Epub 2013 Nov 20.
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.
背景
肺动脉内皮功能障碍已在肺动脉高压（PAH）中得到证实。替米沙坦对 PAH 患者的内皮功能有有益的影响；然而，这些作用的潜在机制尚不清楚。
目的
在这项研究中，我们观察了替米沙坦对单剂量注射野百合碱（MCT）诱导的 Sprague Dawley（SD）大鼠 PAH 模型的影响。
方法
在单次注射 MCT（60mg/kg）后，从第 1 天到第 28 天开始口服替米沙坦（10mg/kg/d），或用 MCT 对照盐水。分析分离的大鼠肺动脉和培养的人肺动脉内皮细胞（HPAEC）中的血管舒张和肺血管重塑；过氧化物酶体增殖物激活受体γ（PPARγ）、Akt、eNOS 的表达；Akt 的磷酸化（p-Akt）和 eNOS 的磷酸化（p-eNOS）水平。
结果
与 MCT 对照组相比，替米沙坦治疗改善了肺动脉内皮功能障碍和重塑，防止了 MCT 引起的右心室收缩压（RVSP）升高。免疫印迹结果表明，单独用 MCT 处理的肺动脉中 PPARγ、p-Akt 和 p-eNOS 水平较低，并用替米沙坦共同处理后水平显著恢复。在分离的肺动脉中，替米沙坦孵育 12 小时可改善肺动脉内皮依赖性血管舒张功能障碍，而这种作用被 PPARγ 或磷酸肌醇 3-激酶（PI3K）信号转导的抑制所阻断。在培养的 HPAEC 中，替米沙坦治疗增加了 PPARγ 的表达，并促进了 Akt 和 eNOS 的磷酸化，从而增加了 NO 的产生。这些作用被 PPARγ 或 PI3K 的抑制所消除。
结论
替米沙坦通过依赖 PPARγ 的 PI3K/Akt/eNOS 途径保护 MCT 诱导的 PAH 中的内皮功能障碍。因此，替米沙坦可能是 PAH 高危患者有前途的治疗策略。
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