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首页> 外文期刊>American Journal of Physiology >Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism.
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Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanism.

机译：Monocrotaline吡咯诱导的内皮细胞巨细胞增多涉及高尔基体阻断机制。

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Pyrrolizidine alkaloids initiate disease in the lung (pulmonary hypertension), liver (veno-occlusive disease and cirrhosis), and kidneys (afferent arteriolar block and mesangiolysis) by inducing a megalocytotic phenotype in target endothelial and parenchymal cells. A "hit-and-run" type of exposure to the bioactive pyrrolizidine results, within 2-3 days, in enlarged cells with large nuclei and enlarged Golgi and endoplasmic reticulum, while the cells remain in G2/M block. In the present study, we recapitulated monocrotaline pyrrole (MCTP)-induced megalocytosis in cultures of bovine pulmonary arterial endothelial cells (PAEC), human Hep3B hepatocytes, human type II-like alveolar epithelial cells (A549), and human pulmonary arterial smooth muscle cells (PASMC) and investigated the subcellular mechanism involved. There was an inverse relationship between reduction in caveolin (Cav)-1 levels and stimulation of promitogenic STAT3 and ERK1/2 cell signaling. In megalocytotic PAEC, the Golgi scaffolding proteinGM130 was shifted from membranes with heavy density to those with a lighter density. This lighter Golgi fraction was enriched for hypo-oligomeric Cav-1, indicating dysfunctional trafficking of cargo. Immunofluorescence imaging studies confirmed the trapping of Cav-1 in a GM130-positive Golgi compartment. There was an increase in Ser25 phosphorylation of GM130 (typically a prelude to Golgi fragmentation and mitosis) and increased association between pGM130, cdc2 kinase, and Cav-1. Nevertheless, megalocytotic MCTP-treated cells showed reduced entry into mitosis upon stimulation with 2-methoxyestradiol (2-ME), reduced 2-ME-induced Golgi fragmentation, and a slowing of Golgi reassembly after nocodazole-induced fragmentation. These data suggest that a disruption of the trafficking and mitosis sensor functions of the Golgi may represent the subcellular mechanism leading to MCTP-induced megalocytosis ("the Golgi blockade hypothesis").
机译：吡咯嗪核生物碱通过在靶内皮细胞和实质细胞中诱导巨噬细胞表型，从而引发肺部疾病（肺动脉高压），肝脏（静脉阻塞性疾病和肝硬化）和肾脏疾病（轻度小动脉阻塞和血管舒张）。在2到3天之内，“活着”暴露于生物活性吡咯烷啶的结果是，细胞增大且细胞核较大，高尔基体和内质网也增大，而细胞仍处于G2 / M阻滞状态。在本研究中，我们概述了牛气瓶吡咯（MCTP）诱导的牛肺动脉内皮细胞（PAEC），人Hep3B肝细胞，人II型样肺泡上皮细胞（A549）和人肺动脉平滑肌细胞培养物中的巨噬细胞增多（PASMC）并研究了涉及的亚细胞机制。降低洞穴蛋白（Cav）-1水平与刺激促有丝分裂的STAT3和ERK1 / 2细胞信号转导之间存在反比关系。在巨细胞PAEC中，高尔基体支架蛋白GM130从高密度的膜转移到了较轻的膜。该较轻的高尔基级分富含低聚Cav-1，表明货物运输不正常。免疫荧光成像研究证实，Cav-1被捕获在GM130阳性高尔基体中。 GM130的Ser25磷酸化增加（通常是高尔基体分裂和有丝分裂的前奏），pGM130，cdc2激酶和Cav-1之间的关联增加。然而，巨细胞吞噬MCTP处理的细胞显示2-甲氧基雌二醇（2-ME）刺激后进入有丝分裂的程度降低，2-ME诱导的高尔基体碎裂减少，诺考达唑诱导的碎片后高尔基体重组减慢。这些数据表明，高尔基体的运输和有丝分裂传感器功能的破坏可能代表了导致MCTP诱导的巨细胞增多的亚细胞机制（“高尔基体阻断假说”）。

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