Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia

Autor: Arun Pradhan, Lixiao Che, Vladimir Ustiyan, Abid A. Reza, Nicole M. Pek, Yufang Zhang, Andrea B. Alber, Timothy R. Kalin, Jennifer A. Wambach, Mingxia Gu, Darrell N. Kotton, Matthew E. Siefert, Assem G. Ziady, Tanya V. Kalin, Vladimir V. Kalinichenko
Rok vydání: 2023
Předmět:
Zdroj: American Journal of Respiratory and Critical Care Medicine. 207:1042-1054
ISSN: 1535-4970
1073-449X
DOI: 10.1164/rccm.202207-1332oc
Popis: Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is linked to heterozygous mutations in the FOXF1 gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed.Identify small molecule compounds that stimulate FOXF1 signaling.We used mass spectrometry, immunoprecipitation, and the in vitro ubiquitination assay to identify TanFe, a small molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and Acute Lung Injury and in human vascular organoids derived from iPSCs of ACDMPV patient.We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1-HECTD1 protein-protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells in vitro. TanFe increased protein levels of FOXF1 and its target genes Flk1, Flt1 and Cdh5 in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein levels in lungs of Foxf1+/- embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of Foxf1+/- mice after birth. TanFe increased angiogenesis in human vascular organoids derived from iPSCs of ACDMPV patient with FOXF1 deletion.TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.
Databáze: OpenAIRE
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