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

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. Translational Perspective The inhibitory effect of PTP4A1 in the dysfunction of vascular endothelial cells could apply to develop a drug for vascular inflammatory diseases including atherosclerosis. This study highlights an alternative as well as an effective therapeutic approach to increase A20 expression, which is an endogenous negative regulator of NF-κB signalling in vascular inflammatory disorders.

USF1 modulates transcription and cellular functions by regulating multiple transcription factors in Huh7 cells

“…It was also demonstrated that USF1 promotes TNFAIP3/A20 expression, and thus inhibits inflammatory NF-κB pathway activity; this regulatory axis is a potential anti-inflammatory strategy for the treatment of several diseases (31). The USF1/A20 regulatory axis was also validated in mitigating vascular inflammation by NF-κB inactivation (32). In HCC, the inflammation can be orchestrated by the tumor itself by secreting factors that recruit inflammatory cells to the tumor favoring the buildup of a microenvironment, and inflammation promotes HCC development by promoting a series of cancer-promoting biological processes (33).…”

Integrative Bioinformatics–Gene Network Approach Reveals Linkage between Estrogenic Endocrine Disruptors and Vascular Remodeling in Peripheral Arterial Disease

“…The activation of PTP4A3 by VEGF is crucial for cellular movement and actin rearrangement in human endothelial cells [39]. Additionally, PTP4A1 is understood to counteract vascular inflammation via upstream stimulatory factor 1 (USF1) [40], underscoring its multifaceted role in regulating cell growth and migration, which are vital to vascular health and disease [40].…”