DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction.
DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction.
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DRD1 下调导致机械拉伸引起的肺内皮屏障功能障碍
DOI：
10.7150/thno.46192
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Jiang L
中科院分区：
文献类型：
--
作者：
Wang Y;Liu YJ;Xu DF;Zhang H;Xu CF;Mao YF;Lv Z;Zhu XY;Jiang L
原理：多巴胺的肺保护作用及其在呼吸机诱导的肺损伤（VILI）病理学中的作用正在显现。然而，其潜在机制在很大程度上仍然未知。目的：目的探讨多巴胺D1受体（DRD 1）激动剂在VILI发病机制中的作用及对VILI的治疗作用。研究方法：多巴胺受体在机械牵张诱导的内皮屏障功能障碍和肺损伤中的作用在DRD 1基因敲除小鼠、分离的小鼠肺血管内皮细胞（MLVECs）和接受肺叶切除术并机械通气不同时间段的患者的肺样本中进行了研究。测量和主要结果：DRD 1在手术患者和暴露于机械通气的小鼠中均下调。预防性给予多巴胺或DRD 1激动剂可减轻机械牵张诱导的肺内皮屏障功能障碍和肺损伤。相比之下，肺敲除或DRD 1的整体敲除加剧了这些作用。预防性给予多巴胺可通过DRD 1信号转导减弱机械牵张诱导的α-微管蛋白脱乙酰化和随后的内皮通透性增高。我们发现，环状牵张诱导的糖原合成酶激酶-3 β激活导致组蛋白脱乙酰酶6（HDAC 6）的磷酸化和激活，从而导致α-微管蛋白的脱乙酰化。激活后，DRD 1信号通过cAMP/交换蛋白激活的cAMP（EPAC）介导的HDAC 6失活，减弱机械牵张诱导的α-微管蛋白脱乙酰化和随后的肺内皮屏障功能障碍。结论：这项工作确定了一种新的保护作用，DRD 1对机械拉伸诱导的肺内皮屏障功能障碍和肺损伤。进一步研究DRD 1参与微管稳定性调节和干扰DRD 1/cAMP/EPAC/HDAC 6信号转导的机制可能为VILI的治疗方法提供见解。
Rationale: The lung-protective effects of dopamine and its role in the pathology of ventilator-induced lung injury (VILI) are emerging. However, the underlying mechanisms are still largely unknown. Objective: To investigate the contribution of dopamine receptor dysregulation in the pathogenesis of VILI and therapeutic potential of dopamine D1 receptor (DRD1) agonist in VILI. Methods: The role of dopamine receptors in mechanical stretch-induced endothelial barrier dysfunction and lung injury was studied in DRD1 knockout mice, in isolated mouse lung vascular endothelial cells (MLVECs), and in lung samples from patients who underwent pulmonary lobectomy with mechanical ventilation for different time periods. Measurements and Main Results: DRD1 was downregulated in both surgical patients and mice exposed to mechanical ventilation. Prophylactic administration of dopamine or DRD1 agonist attenuated mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. By contrast, pulmonary knockdown or global knockout of DRD1 exacerbated these effects. Prophylactic administration of dopamine attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent endothelial hyperpermeability through DRD1 signaling. We identified that cyclic stretch-induced glycogen-synthase-kinase-3β activation led to phosphorylation and activation of histone deacetylase 6 (HDAC6), which resulted in deacetylation of α-tubulin. Upon activation, DRD1 signaling attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent lung endothelial barrier dysfunction through cAMP/exchange protein activated by cAMP (EPAC)-mediated inactivation of HDAC6. Conclusions: This work identifies a novel protective role for DRD1 against mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. Further study of the mechanisms involving DRD1 in the regulation of microtubule stability and interference with DRD1/cAMP/EPAC/HDAC6 signaling may provide insight into therapeutic approaches for VILI.
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影响因子：
5.8
作者：
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通讯作者：
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DOI：
10.1165/rcmb.2015-0149oc
发表时间：
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影响因子：
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作者：
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DOI：
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发表时间：
2013-12-01
影响因子：
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DOI：
10.1038/s41580-018-0009-y
发表时间：
2018-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
Brouhard GJ;Rice LM
通讯作者：
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