The p53 pathway in vasculature revisited: A therapeutic target for pathological vascular remodeling?

Cui, Xiaopei; Pan, Guopin; Chen, Ye; Guo, Xinfeng; Liu, Tengfei; Zhang, Jing; Yang, Xiaofan; Cheng, Mei; Gao, Haiqing; Jiang, Fan

doi:10.1016/j.phrs.2021.105683

Cited by 10 publications

(13 citation statements)

References 147 publications

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“…GO and KEGG analyses on the CX-5461-responsive genes similarly identified enrichment in biological processes related to cell cycle regulation (GO: cell cycle phase transition; KEGG: cell cycle), which were highly statistically significant (Table 1). Consistent with previous data suggesting that activation of the p53 pathway had a pivotal role in mediating the pharmacological effects of CX-5461 (Bywater et al, 2012;Tsai and Pederson, 2014;Ye et al, 2017;Cui et al, 2021;Pang et al, 2021;Xu et al, 2021), we also showed that a cluster of 6 genes associated with p53 signaling (KEGG: p53 signaling pathway) were significantly altered by CX-5461 in both LPSand IFN-γ-primed cells. These p53-related genes included CDKN1A (cyclin-dependent kinase inhibitor 1/p21 Cip1 ), CDK1 (cyclin-dependent kinase 1/Cdk1), CCNE2 (cyclin E2), CCNE1 (cyclin E1), RRM2 (ribonucleotide reductase regulatory subunit M2) and CCNB1 (cyclin B1).…”

Section: Cx-5461 Treatment Resulted In Overlapping Transcriptome Sign...supporting

confidence: 91%

“…Consistent with our experimental results, there is evidence showing that p53 activation exhibits anti-inflammatory properties under various pathologic conditions [reviewed recently in ( Cui et al, 2021 )]. In macrophages, p53 may produce anti-inflammatory effects by downregulating the expression of STAT-1 (signal transducer and activator of transcription 1) ( Zheng et al, 2005 ).…”

Section: Introductionsupporting

confidence: 92%

“…Although the available data regarding the role of p53 in modulating inflammatory reactions appear to be controversial, a mass of evidence suggests that p53 has anti-inflammatory activities in certain pathological contexts (see Cui et al, 2021 ). In a recent study we have shown that CX-5461 can inhibit T cell-mediated immunity functions via p53-DUSP5 (dual-specificity phosphatase 5) axis and subsequent antagonism of the Erk1/2 mitogen-activated protein kinase activity, thereby preventing the occurrence of acute transplant rejection ( Pan et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

Wang

Zhi-Jian²,

Cui³

et al. 2022

Front. Pharmacol.

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CX-5461, a novel selective RNA polymerase I inhibitor, shows potential anti-inflammatory and immunosuppressive activities. However, the molecular mechanisms underlying the inhibitory effects of CX-5461 on macrophage-mediated inflammation remain to be clarified. In the present study, we attempted to identify the systemic biological processes which were modulated by CX-5461 in inflammatory macrophages. Primary peritoneal macrophages were isolated from normal Sprague Dawley rats, and primed with lipopolysaccharide or interferon-γ. Genome-wide RNA sequencing was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used for gene functional annotations. Enrichment analysis was conducted using the ClusterProfiler package of R software. We found that CX-5461 principally induced a molecular signature related to cell cycle inhibition in primed macrophages, featuring downregulation of genes encoding cell cycle mediators and concomitant upregulation of cell cycle inhibitors. At the same concentration, however, CX-5461 did not induce a systemic anti-inflammatory transcriptional program, although some inflammatory genes such as IL-1β and gp91phox NADPH oxidase were downregulated by CX-5461. Our data further highlighted a central role of p53 in orchestrating the molecular networks that were responsive to CX-5461 treatment. In conclusion, our study suggested that limiting cell proliferation predominated in the inhibitory effects of CX-5461 on macrophage-mediated inflammation.

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Section: Cx-5461 Treatment Resulted In Overlapping Transcriptome Sign...supporting

confidence: 91%

Section: Introductionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

Wang

Zhi-Jian²,

Cui³

et al. 2022

Front. Pharmacol.

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View full text Add to dashboard Cite

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“…Despite the new findings reported here, the potential limitations of this study should be noted. First, although JNJ-165 treatment suppressed ox-LDL-induced mitochondrial damage and inflammation in HAECs independent of p53, we cannot exclude the possible role of p53 in the protective effect of JNJ-165 against atherosclerosis by other mechanisms in different aortic cells, since this gene is involved in many signaling pathways that cause cell senescence, apoptosis and cell cycle arrest in the pathogenesis of atherosclerosis [ 35 ]. Thus, further investigations are needed.…”

Section: Discussionmentioning

confidence: 99%

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

Zhang

Cao

et al. 2022

IJMS

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A novel function of retinoid X receptor beta (RXRβ) in endothelial cells has been reported by us during the formation of atherosclerosis. Here, we extended the study to explore the cellular mechanisms of RXRβ protein stability regulation. In this study, we discovered that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RXRβ for degradation. The result showed that MDM2 directly interacted with and regulated RXRβ protein stability. MDM2 promoted RXRβ poly-ubiquitination and degradation by proteasomes. Moreover, mutated MDM2 RING domain (C464A) or treatment with an MDM2 inhibitor targeting the RING domain of MDM2 lost the ability of MDM2 to regulate RXRβ protein expression and ubiquitination. Furthermore, treatment with MDM2 inhibitor alleviated oxidized low-density lipoprotein-induced mitochondrial damage, activation of TLR9/NF-κB and NLRP3/caspase-1 pathway and production of pro-inflammatory cytokines in endothelial cells. However, all these beneficial effects were reduced by the transfection of RXRβ siRNA. Moreover, pharmacological inhibition of MDM2 attenuated the development of atherosclerosis and reversed mitochondrial damage and related inflammation in the atherosclerotic process in LDLr-/- mice, along with the increased RXRβ protein expression in the aorta. Therefore, our study uncovers a previously unknown ubiquitination pathway and suggests MDM2-mediated RXRβ ubiquitination as a new therapeutic target in atherosclerosis.

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“…Pulmonary vasodilation is closely related to the regulatory role of PAECs, but the biological mechanism of Piezo1 in PASMCs is unclear. It has been proposed that alterations in hemodynamics cause endothelial damage in the pulmonary vasculature to some extent and also play a regulatory role in the phenotypic transformation and morphological structure of PASMCs, and that hemodynamics are also necessary for the development and maintenance of vascular remodeling in pulmonary hypertension ( 105 , 108 , 109 ). It has been hypothesized that one of the important factors contributing to pulmonary artery remodeling is the increase in intracellular free calcium concentration ([Ca 2+ ] i) caused by mechanical stimulation of PASMCs ( 93 , 94 ).…”

Section: Pharmacological Modulators Of Piezo1 Channelsmentioning

confidence: 99%

Piezo1 in vascular remodeling of atherosclerosis and pulmonary arterial hypertension: A potential therapeutic target

Han

Hong

et al. 2022

Front. Cardiovasc. Med.

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Vascular remodeling (VR) is a structural and functional change of blood vessels to adapt to the changes of internal and external environment. It is one of the common pathological features of many vascular proliferative diseases. The process of VR is mainly manifested in the changes of vascular wall structure and function, including intimal hyperplasia, thickening or thinning of media, fibrosis of adventitia, etc. These changes are also the pathological basis of aging and various cardiovascular diseases. Mechanical force is the basis of cardiovascular biomechanics, and the newly discovered mechanical sensitive ion channel Piezo1 is widely distributed in the whole cardiovascular system. Studies have confirmed that Piezo1, a mechanically sensitive ion channel, plays an important role in cardiovascular remodeling diseases. This article reviews the molecular mechanism of Piezo1 in atherosclerosis, hypertension and pulmonary hypertension, in order to provide a theoretical basis for the further study of vascular remodeling.

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The p53 pathway in vasculature revisited: A therapeutic target for pathological vascular remodeling?

Cited by 10 publications

References 147 publications

A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

Piezo1 in vascular remodeling of atherosclerosis and pulmonary arterial hypertension: A potential therapeutic target

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