MicroRNA-1 protects the endothelium in acute lung injury
Asawari Korde, … , Richard W. Pierce, Shervin S. Takyar
Asawari Korde, … , Richard W. Pierce, Shervin S. Takyar
Published September 22, 2023
Citation Information: JCI Insight. 2023;8(18):e164816. https://doi.org/10.1172/jci.insight.164816.
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Research Article Pulmonology Vascular biology

MicroRNA-1 protects the endothelium in acute lung injury

Abstract

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung, and vascular endothelial growth factor (VEGF) is elevated in ARDS. We found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1), were reduced in the lung endothelium after acute injury. Pulmonary endothelial cell–specific (EC-specific) overexpression of miR-1 protected the lung against cell death and barrier dysfunction in both murine and human models and increased the survival of mice after pneumonia-induced ALI. miR-1 had an intrinsic protective effect in pulmonary and other types of ECs; it inhibited apoptosis and necroptosis pathways and decreased capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoietin-2 (ANGPT2), CNKSR family member 3 (CNKSR3), and TNF-α–induced protein 2 (TNFAIP2). We validated miR-1–mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate a previously unknown role of miR-1 as a cytoprotective orchestrator of endothelial responses to acute injury with prognostic and therapeutic potential.

Authors

Asawari Korde, Maria Haslip, Prachi Pednekar, Alamzeb Khan, Maurizio Chioccioli, Sameet Mehta, Francesc Lopez-Giraldez, Santos Bermejo, Mauricio Rojas, Charles Dela Cruz, Michael A. Matthay, Jordan S. Pober, Richard W. Pierce, Shervin S. Takyar

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Figure 2

Lung injury downregulates miR-1 in endothelial cells.

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Lung injury downregulates miR-1 in endothelial cells. (A) Human ex vivo–...
(A) Human ex vivo–cultured lungs were treated with LPS (500 ng/mL) or vehicle (PBS) for 24 hours. Endothelial (CD45–CD31+) and immune (CD45+) cells were isolated and miR-1 levels measured as described in Figure 1 (n = 3 patients). *P = 0.008. (B) Lung endothelial miR-1 in hyperoxia (HO) model; RA, room air (n ≥ 3). *P = 0.004. (C) Lung endothelial miR-1 in the E. coli model (n = 3 PBS, 4 for E. coli). *P = 0.0325. (D–F) Endothelial cells were treated with increasing concentrations of LPS for 24 hours and miR-1 levels were measured and expressed as described in A. (D) MLECs (n ≥ 4, from 2 experiments). *P = 0.0339, **P = 0.0019, ***P = 0.0097. (E) HPMECs (n ≥ 8 from 3 experiments). *P = 0.02, **P < 0.0001. (F) HUVECs (n = 6). *P = 0.02, **P = 0.008. (G) HDMECs (n = 12, from 2 experiments). *P = 0.0005, **P = 0.0001. (H) HPMECs were treated with increasing concentrations of TNF-α for 24 hours and mature miR-1 levels were measured, analyzed, and expressed as in A (n = 3). *P < 0.05. Error bars represent the SEM. Data were analyzed by unpaired, 2-tailed t test with Welch’s correction or Mann-Whitney U test based on normality.