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SIX1 drives endothelial dysfunction via MAST4/MAPK 1/3 axis to promote pulmonary artery hypertension

ABSTRACT: Increasing evidences support that endothelial dysfunction initiates and drives pulmonary vascular remodeling. Targeting endothelial dysfunction is a promising treatment strategy for pulmonary artery hypertension (PAH). Therefore, it is urgent to elucidate the pathological mechanism of endothelial dysfunction. SIX1 is a critical transcription factor that regulates pulmonary vascular development. Lack of SIX1 impairs the differentiation of pulmonary vascular endothelial cells into smooth muscle cells. However, the role of SIX1 in endothelial dysfunction and PAH is unknown. In this study, we confimed that SIX1 was a critical transicription factor to induced endothelial dysfunction and PAH, and uncoverd that MAST4 was the target of SIX1-mediating endothelial dysfunction. MAST4 is a serine/threonine kinase, however the underlying mechanism by which MAST4 mediated endothelial dysfunction was unknown. Therefore, we planed to perform phosphoproteomics to explore the underlying mechanism.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ting Liu

PROVIDER: PXD053267 | iProX | Thu Jun 20 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, however, the mechanism remains unknown. In this study, we hypothesized that the ultrafine fraction of ambient pollutant particles would cause endothelial cells dysfunction. We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine Chapel Hill particles (UFP) (100Î¼g/ml) or vehicle for 4h with Affymetrix HG U133 Plus 2.0 chips (N = 4 each). Using an unpaired t-test (p <0.01, 5% false discovery rate) we found 426 unique genes to be differentially expressed with 320 upregulated genes and 106 downregulated genes. Among these genes, we noted upregulation of genes related to coagulation-inflammation circuitry including tissue factor (F3), coagulation factor II receptor-like 2 (F2RL2, PAR3), interleukin (IL)-6 and IL-8. Upregulation of these genes were independently confirmed by RT-PCR and/or protein release. Genes related to the CXC chemokine family that have been implicated in the pathogenesis of vascular disease were upregulated, including MCP-1 (2.60 fold), IL-8 (2.47 fold), CXCL1 (1.41 fold), CXCL2 (1.95 fold), CXCL3 (2.28 fold) and CXCR4 (1.30 fold). In addition, genes related to clotting independent signaling of F3 were also differentially expressed, including FOS, JUN and NFKBIA. Treatment of HPAEC with UFP for 16 hours increased the release of IL6 and IL8 by 1.9-fold and 1.8-fold respectively. Pretreatment of HPAEC with a blocking antibody against F3 attenuated IL6 and IL8 release by 30% and 70% respectively. Thus using gene profiling, we uncovered that UFP may induce vascular endothelial cells to express genes related to clotting and angiogenesis. These results provide a novel hypothesis that PM may cause cardiovascular adverse health effects via induction of tissue factor in vascular endothelial cells which then triggers clotting dependent and independent downstream signaling. Experiment Overall Design: Human pulmonary artery endothelial cell cultures were treated with Chapel Hill Ultrafine particles or with vehicle control for 4h. 4 bological replicates each for treatment (100ug/ml) and control. 8 affy chips total.

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SIX1 drives endothelial dysfunction via MAST4/MAPK 1/3 axis to promote pulmonary artery hypertension

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