Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation

Min Ji Cho, Dong Gwang Lee, Jeong Woong Lee, Byungtae Hwang, Sung Jin Yoon, Seon Jin Lee, Young Jun Park, Seung Ho Park, Hee Gu Lee, Yong Hoon Kim, Chul Ho Lee, Jangwook Lee, Nam Kyung Lee, Tae Su Han, Hyun Soo Cho, Jeong Hee Moon, Ga Seul Lee, Kwang Hee Bae, Geum Sook Hwang, Sang Hak LeeSang J. Chung, Sungbo Shim, Jaehyung Cho, Goo Taeg Oh, Young Guen Kwon, Jong Gil Park, Jeong Ki Min

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Aims The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. Methods and results In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

Original languageEnglish
Pages (from-to)1265-1278
Number of pages14
JournalCardiovascular Research
Volume119
Issue number5
DOIs
StatePublished - 1 May 2023

Keywords

  • Atherosclerosis
  • Cell adhesion molecules
  • Endothelial cells
  • Protein phosphatase
  • Vascular inflammation

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