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  • 标题:Splice factor polypyrimidine tract-binding protein 1 (Ptbp1) primes endothelial inflammation in atherogenic disturbed flow conditions
  • 本地全文:下载
  • 作者:Jessica A. Hensel ; Sarah-Anne E. Nicholas ; Amy L. Kimble
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2022
  • 卷号:119
  • 期号:30
  • DOI:10.1073/pnas.2122227119
  • 语种:English
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:Significance Plaque forms in low and disturbed flow regions of the vasculature, where platelets adhere and endothelial cells are “primed” to respond to cytokines (e.g., tumor necrosis factor-α) with elevated levels of cell adhesion molecules via the NF-κB signaling pathway. We show that the splice factor polypyrimidine tract binding protein (Ptbp1; purple) mediates priming. Ptbp1 is induced in endothelial cells by platelet recruitment, promoting priming and subsequent myeloid cell infiltration into plaque. Mechanistically, Ptbp1 regulates splicing of genes (e.g., Ripk1) involved in the NF-κB signaling pathway and is required for efficient nuclear translocation of NF-κB in endothelial cells. This provides new insight into the molecular mechanisms underlying an endothelial priming process that reinforces vascular inflammation. NF-κB–mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through adhesion molecules Icam1 and Vcam1. The endothelium is primed for cytokine activation of NF-κB by exposure to low and disturbed blood flow (LDF)but the molecular underpinnings are not fully understood. In an experimental in vivo model of LDF, platelets were required for the increased expression of several RNA-binding splice factors, including polypyrimidine tract binding protein (Ptbp1). This was coordinated with changes in RNA splicing in the NF-κB pathway in primed cells, leading us to examine splice factors as mediators of priming. Using Icam1 and Vcam1 induction by tumor necrosis factor (TNF)-α stimulation as a readout, we performed a CRISPR Cas9 knockout screen and identified a requirement for Ptbp1 in priming. Deletion of Ptbp1 had no effect on cell growth or response to apoptotic stimuli, but reversed LDF splicing patterns and inhibited NF-κB nuclear translocation and transcriptional activation of downstream targets, including Icam1 and Vcam1. In human coronary arteries, elevated PTBP1 correlates with expression of TNF pathway genes and plaque. In vivo, endothelial-specific deletion of Ptbp1 reduced Icam1 expression and myeloid cell infiltration at regions of LDF in atherosclerotic mice, limiting atherosclerosis. This may be mediated, in part, by allowing inclusion of a conserved alternative exon in Ripk1 leading to a reduction in Ripk1 protein. Our data show that Ptbp1, which is induced in a subset of the endothelium by platelet recruitment at regions of LDF, is required for priming of the endothelium for subsequent NF-κB activation, myeloid cell recruitment and atherosclerosis.
  • 关键词:enendothelialalternative splicinginflammationatherosclerosisplatelets
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