Dysregulation of PTEN in cardiopulmonary vascular remodeling induced by pulmonary hypertension.
Dysregulation of PTEN in cardiopulmonary vascular remodeling induced by pulmonary hypertension.
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DOI：
10.1007/s12013-011-9332-z
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发表时间：
2013-11
影响因子：
2.6
通讯作者：
Kuppusamy P
中科院分区：
文献类型：
--
作者：
Ravi Y;Selvendiran K;Meduru S;Citro L;Naidu S;Khan M;Rivera BK;Sai-Sudhakar CB;Kuppusamy P
肺动脉高压（PH）是一种以动脉狭窄为特征的肺血管疾病。10号染色体上的磷酸酶与张力蛋白同源物（PTEN）与多种癌症的进展有关，也涉及动脉重塑。然而，PTEN在肺动脉高压中的作用仍不清楚。本研究的目的是利用已建立的肺动脉高压模型确定PTEN在肺血管重塑中的作用。该研究使用了由野百合碱（MCT）给药（60mg/kg）或持续缺氧暴露（10%氧气）3周诱导的大鼠肺动脉高压模型。肺动脉平滑肌细胞（SMCs）用于体外验证。通过血流动力学、形态学和组织病理学分析验证了肺动脉高压的发展。通过蛋白质印迹和逆转录 - 聚合酶链反应分析肺和心脏组织中的PTEN及关键下游蛋白。在肺动脉高压大鼠的组织中，PTEN显著降低（MCT组，53%；缺氧组，40%），磷酸化蛋白激酶B（pAkt）显著升高（MCT组，42%；缺氧组，55%）。在缺氧（1%氧气）暴露48小时的平滑肌细胞中也观察到了类似结果。泛素化试验表明PTEN通过蛋白酶体降解途径降解。蛋白质印迹显示在两种模型的肺中，细胞周期调节蛋白p53和p27显著下调，细胞周期蛋白D1上调。结果表明PTEN介导的磷脂酰肌醇 - 3 - 激酶（PI3K）通路的调节不依赖于黏着斑激酶和脂肪酸合酶。该研究首次证实PTEN在肺动脉高压的进展中起关键作用。这些发现可能为以PTEN为靶点治疗肺动脉高压提供潜在可能。
Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.