Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension
Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension
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DOI：
10.1152/ajplung.00428.2006
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Erzurum, Serpil C.
中科院分区：
文献类型：
--
作者：
Masri, Fares A.;Xu, Weiling;Erzurum, Serpil C.
特发性肺动脉高压（IPAH）的特征是丛状血管病变，这被假设是由肺动脉内皮细胞（PAEC）生长失调引起的。在此，评估了来自IPAH和对照人肺的PAEC之间的功能和分子差异。与对照细胞相比，IPAH PAEC有更大的细胞数量在响应于培养中的生长因子，由于增加增殖所确定的溴脱氧尿苷掺入和Ki 67核抗原表达和减少凋亡所确定的caspase-3激活和TdT介导的dUTP缺口末端标记试验。在体外血管生成试验中，IPAH细胞的迁移能力比对照细胞强，但管状结构的形成较弱。在IPAH PAEC中鉴定了信号转导子和转录激活子3（STAT 3）的持续激活，STAT 3是细胞存活和血管生成的调节因子，并且其下游促存活靶点Mcl-1的表达增加。Janus激酶（JAK）选择性抑制剂减少了STAT 3的激活并阻断了IPAH细胞的增殖。在体内IPAH病变的内皮细胞中检测到磷酸化的STAT 3，表明STAT 3活化在IPAH肺的增殖性肺血管病变中起作用。
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.