Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS-CoV-2 infection.
Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS-CoV-2 infection.
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DOI：
10.1002/pul2.12071
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发表时间：
2022-04
影响因子：
2.6
通讯作者：
Maron, Bradley A.
中科院分区：
文献类型：
--
作者：
Alba, George A.;Samokhin, Andriy O.;Wang, Rui-Sheng;Wertheim, Bradley M.;Haley, Kathleen J.;Padera, Robert F.;Vargas, Sara O.;Rosas, Ivan O.;Hariri, Lida P.;Shih, Angela;Thompson, Boyd Taylor;Mitchell, Richard N.;Maron, Bradley A.
严重急性呼吸综合征冠状病毒- 2 （SARS - CoV - 2）感染引起的急性呼吸窘迫综合征（ARDS）原位肺血栓形成的病理生物学尚未完全确定。在人肺动脉内皮细胞（HPAECs）中，缺氧增加神经前体细胞表达，发育下调9 (NEDD9)，并诱导细胞外质膜表面血栓形成前NEDD9肽（N9P）的表达。我们假设SARS - CoV - 2-ARDS病理型与肺内皮N9P增高有关。石蜡包埋尸检肺标本来自SARS - CoV - 2 - ARDS患者（n = 13），其他原因的ARDS患者（n = 10）和器官供体对照（n = 5）。免疫荧光表征了N9P、纤维蛋白和转录因子12 （TCF12）的表达，TCF12是SARS‐CoV‐2的推定结合靶点，也是已知的NEDD9的转录调节因子。我们对正常的HPAECs进行了RNA测序，这些HPAECs在常氧或缺氧（0.2% O2）下处理了24小时。免疫沉淀-液相色谱-质谱（IP - LC - MS）分析了与血栓稳定相关的N9P蛋白相互作用。与正常缺氧相比，体外HPAECs缺氧显著增加了TCF12信使RNA(+1.19倍，p = 0.001；假发现率= 0.005)，SARS - CoV - 2-ARDS肺内皮TCF12表达比供体对照肺增加了3倍（p < 0.001）。与供体对照相比，非SARS - CoV - 2-ARDS和SARS - CoV - 2-ARDS患者肺内皮N9P -纤维蛋白原位共定位增加（3.7±1.2比10.3±3.2和21.8±4.0 arb）。单位，p < 0.001)。然而，与供体对照相比，仅在SARS - CoV - 2-ARDS组，肺内皮总N9P显著升高（15±4.2 vs 6.3±0.9 arb）。单位，p < 0.001)。在HPAEC质膜分离物中，IP‐LC‐MS鉴定出NEDD9和αvβ3‐整合素的β3‐亚基之间的一种新的蛋白-蛋白相互作用，αvβ3‐整合素调节纤维蛋白锚定在内皮细胞上。结论：致死性SARS - CoV - 2-ARDS与肺内皮细胞N9P表达增加和N9P -纤维蛋白原位共定位有关。需要进一步的研究来确定N9P与SARS - CoV - 2-ARDS血栓形成病理型的发病和潜在的治疗相关性。
The pathobiology of in situ pulmonary thrombosis in acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is incompletely characterized. In human pulmonary artery endothelial cells (HPAECs), hypoxia increases neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and induces expression of a prothrombotic NEDD9 peptide (N9P) on the extracellular plasma membrane surface. We hypothesized that the SARS‐CoV‐2–ARDS pathophenotype involves increased pulmonary endothelial N9P. Paraffin‐embedded autopsy lung specimens were acquired from patients with SARS‐CoV‐2–ARDS (n = 13), ARDS from other causes (n = 10), and organ donor controls (n = 5). Immunofluorescence characterized the expression of N9P, fibrin, and transcription factor 12 (TCF12), a putative binding target of SARS‐CoV‐2 and known transcriptional regulator of NEDD9. We performed RNA‐sequencing on normal HPAECs treated with normoxia or hypoxia (0.2% O2) for 24 h. Immunoprecipitation‐liquid chromatography‐mass spectrometry (IP‐LC‐MS) profiled protein–protein interactions involving N9P relevant to thrombus stabilization. Hypoxia increased TCF12 messenger RNA significantly compared to normoxia in HPAECs in vitro (+1.19‐fold, p = 0.001; false discovery rate = 0.005), and pulmonary endothelial TCF12 expression was increased threefold in SARS‐CoV‐2–ARDS versus donor control lungs (p < 0.001). Compared to donor controls, pulmonary endothelial N9P‐fibrin colocalization was increased in situ in non‐SARS‐CoV‐2–ARDS and SARS‐CoV‐2–ARDS decedents (3.7 ± 1.2 vs. 10.3 ± 3.2 and 21.8 ± 4.0 arb. units, p < 0.001). However, total pulmonary endothelial N9P was increased significantly only in SARS‐CoV‐2–ARDS versus donor controls (15 ± 4.2 vs. 6.3 ± 0.9 arb. units, p < 0.001). In HPAEC plasma membrane isolates, IP‐LC‐MS identified a novel protein–protein interaction between NEDD9 and the β3‐subunit of the αvβ3‐integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS‐CoV‐2–ARDS is associated with increased pulmonary endothelial N9P expression and N9P‐fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9P to the thrombotic pathophenotype of SARS‐CoV‐2–ARDS.
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影响因子：
8
作者：
Li, Y.;Bavarva, J. H.;Wang, Z.;Guo, J.;Qian, C.;Thibodeau, S. N.;Golemis, E. A.;Liu, W.
通讯作者：
Liu, W.
DOI：
10.1073/pnas.2025581118
发表时间：
2021-05-11
影响因子：
11.1
作者：
Morselli Gysi D;do Valle Í;Zitnik M;Ameli A;Gan X;Varol O;Ghiassian SD;Patten JJ;Davey RA;Loscalzo J;Barabási AL
通讯作者：
Barabási AL
影响因子：
4.8
作者：
Maron, Bradley A.;Zhang, Ying-Yi;Leopold, Jane A.
通讯作者：
Leopold, Jane A.
影响因子：
20.3
作者：
Manalo, DJ;Rowan, A;Semenza, GL
通讯作者：
Semenza, GL
DOI：
10.1016/s2213-2600(20)30370-2
发表时间：
2020-12
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Grasselli G;Tonetti T;Protti A;Langer T;Girardis M;Bellani G;Laffey J;Carrafiello G;Carsana L;Rizzuto C;Zanella A;Scaravilli V;Pizzilli G;Grieco DL;Di Meglio L;de Pascale G;Lanza E;Monteduro F;Zompatori M;Filippini C;Locatelli F;Cecconi M;Fumagalli R;Nava S;Vincent JL;Antonelli M;Slutsky AS;Pesenti A;Ranieri VM;collaborators
通讯作者：
collaborators