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Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Pulm+Circ 2022 ; 12 (2): e12071 Nephropedia Template TP
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Pulmonary endothelial NEDD9 and the prothrombotic pathophenotype of acute respiratory distress syndrome due to SARS-CoV-2 infection #MMPMID35599981
Alba GA; Samokhin AO; Wang RS; Wertheim BM; Haley KJ; Padera RF; Vargas SO; Rosas IO; Hariri LP; Shih A; Thompson BT; Mitchell RN; Maron BA
Pulm Circ 2022[Apr]; 12 (2): e12071 PMID35599981show ga
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 (N9(P)) on the extracellular plasma membrane surface. We hypothesized that the SARS-CoV-2-ARDS pathophenotype involves increased pulmonary endothelial N9(P). 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 N9(P), 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% O(2)) for 24 h. Immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC-MS) profiled protein-protein interactions involving N9(P) 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 N9(P)-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 N9(P) 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 beta(3)-subunit of the alpha(v)beta(3)-integrin, which regulates fibrin anchoring to endothelial cells. In conclusion, lethal SARS-CoV-2-ARDS is associated with increased pulmonary endothelial N9(P) expression and N9(P)-fibrin colocalization in situ. Further investigation is needed to determine the pathogenetic and potential therapeutic relevance of N9(P) to the thrombotic pathophenotype of SARS-CoV-2-ARDS.