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Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

ABSTRACT: Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

PROVIDER: PRJNA954373 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24135757_1.fastq.gz	Fastqsanger.gz
	SRR24135757_2.fastq.gz	Fastqsanger.gz
	SRR24135758_1.fastq.gz	Fastqsanger.gz
	SRR24135758_2.fastq.gz	Fastqsanger.gz
	SRR24135759_1.fastq.gz	Fastqsanger.gz

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Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

Project description:To investigate the effect of Mitomycin-C induced DNA damage on human pulmonary microvascular endothelial cells (hPMVECs), we treated the hPMVECs with 150µM MMC for 0h, 4h, and 14. Saline was used as vehicle. We then performed RNA expression profile analysis using data obtained from RNA-seq of time dependendent MMC treated PMVECs.

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Project description:Biallelic mutations in eukaryotic translation initiation factor 2 α kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these remain uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2-/- adventitial fibroblasts were inflammatory, and therefore we went on to demonstrate a pro-inflammatory phenotype in gcn2-/- mouse embryonic fibroblasts and gcn2-/- mice. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2-/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both baseline and LPS-exaggerated pulmonary hypertensive phenotype. In an orthogonal murine model of pulmonary hypertension induced by exposure to mitomycin-C, deletion of interleukin-6 again rescued the pulmonary vascular phenotype. Targeting Il6-dependent pathways may be useful in treating this deadly disease.

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