首页> 外文期刊>American Journal of Physiology >Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension.
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Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension.

机译:辛伐他汀引起内皮细胞凋亡并减轻严重的肺动脉高压。

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Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.
机译:严重肺动脉高压(SPH)的特征是毛细血管前小动脉腔闭塞,右心室肥大和心包积液。我们最近发表的SPH大鼠模型概括了人类疾病的主要成分。我们使用此模型来开发SPH的新治疗策略。使用VEGF受体阻滞剂与慢性缺氧相结合可诱导大鼠SPH。该研究中使用的多种药物,包括抗癌药(环磷酰胺和紫杉醇),血管紧张素转换酶抑制剂赖诺普利,抗血管生成剂沙利度胺和过氧化物酶体增殖物激活受体-γ激动剂PGJ2,均未能降低平均肺动脉压力(PAP)或右心室肥大。相反,用辛伐他汀治疗已建立SPH的大鼠明显减少了平均PAP和右室肥大,并且这种减少与caspase-3激活和肺微血管内皮细胞凋亡有关。辛伐他汀可部分恢复血管壁中的小窝蛋白1,小窝蛋白2和磷酸小管蛋白表达。在大鼠原发性肺微血管内皮细胞中,辛伐他汀诱导caspase 3激活和Rac 1表达,同时抑制Rho A并减弱Akt和ERK磷酸化水平。我们得出的结论是,辛伐他汀可有效诱导过度增生的肺血管病变中的细胞凋亡,可被视为治疗人类SPH的潜在药物。

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