Oxidized DNA Precursors Cleanup by NUDT1 Contributes to Vascular Remodeling in Pulmonary Arterial Hypertension

Vitry, Géraldine; Paulin, Roxane; Grobs, Yann; Lampron, Marie-Claude; Shimauchi, Takashi; Lemay, Sarah-Eve; Tremblay, Ève; Habbout, Karima; Awada, Charifa; Bourgeois, Alice; Nadeau, Valérie; Paradis, Renée; Roux‐Dalvai, Florence; Orcholski, Mark; Potus, François; Provencher, Steeve; Boucherat, Olivier; Bonnet, Sébastien

doi:10.1164/rccm.202003-0627oc

Cited by 26 publications

(20 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, Survivin and E2F1, found to be significantly downregulated by RNA-Seq, were significantly decreased by Western blot but not by LC-MS/MS proteomics. Importantly, we found that numerous transcripts of genes already known to be implicated in the pro-proliferative and apoptosisresistant phenotype of PAH-PASMCs, such as Survivin [21], ADAMTS8 [35], PBK [20], TK1 [36], and E2F1 [37], were significantly repressed under EZH2 inhibition, which is consistent with the hypothesis that EZH2 plays a critical role in the abnormal phenotype of disease cells. Furthermore, several factors implicated in the protection of DNA damage or in DNA repair itself were diminished.…”

Section: Discussionsupporting

confidence: 88%

“…Not surprisingly, only a small number of genes was found to be dysregulated at both the transcription and translation levels with all these genes exhibiting the same direction of change at the two levels ( Figure 4C). To confirm the robustness and sensitivity of the expression changes observed in our proteomic data sets, expression levels of six DEPs (ROCK1, ROCK2, OGDH, GLS, KPNA2, and FAM49B), already known to be implicated in the pro-proliferative and apoptosis-resistant phenotype of PAH-PASMC or cancer cells [6,20,26,27], were measured by Western blotting in six different PAH-PASMC lines (including the four used in our unbiased proteomic approach). Consistent with the results of LC-MS/MS proteomics, ROCK1, ROCK2, KPNA2, OGDH, and GLS were significantly downregulated in siEZH2treated PAH-PASMCs, whereas FAM49B was augmented ( Figure 4D).…”

Section: Analysis Of Siezh2-associated Proteome Changes By Quantitatimentioning

confidence: 99%

“…Indeed, expression levels of multiple genes found to be upregulated and implicated in the pro-proliferative and apoptosis resistant phenotype of PAH-PASMCs were downregulated in siEZH2-treated cells. These include members of the minichromosome maintenance (MCM) family (MCM2 to MCM7), pituitary tumor-transforming gene 1 (PTTG1), ribonucleotide reductase regulatory subunit M2 (RRM2), thymidine kinase 1 (TK1), and Survivin [20,21]. In terms of molecular function, the downregulated DEGs were enriched in "protein binding", "microtubule binding", and "DNA helicase activity" ( Figure S3B).…”

Section: Impact Of Molecular Inhibition Of Ezh2 On the Pah-pasmc Tranmentioning

confidence: 99%

“…Animal experiments were approved by the Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval Biosafety and Ethics Committees (#2019-018). To induce pulmonary hypertension, adult Sprague Dawley rats (Charles River laboratories, Laval, QC, Canada) were injected with monocrotaline (MCT, 60 mg/kg s.c.) or injected with SU5416 (20 mg/kg s.c.) before exposition to normobaric hypoxia for 3 weeks, as previously described [20]. Experiments were terminated 4 and 5 weeks after MCT or SU5416 injection, respectively.…”

Section: Human Lung Samples and Animal Modelsmentioning

confidence: 99%

See 3 more Smart Citations

Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach

Habbout

Omura

Awada

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Analysis Of Siezh2-associated Proteome Changes By Quantitatimentioning

confidence: 99%

Section: Impact Of Molecular Inhibition Of Ezh2 On the Pah-pasmc Tranmentioning

confidence: 99%

Section: Human Lung Samples and Animal Modelsmentioning

confidence: 99%

See 2 more Smart Citations

Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach

Habbout

Omura

Awada

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, expression of the DNA damage response sensors MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5, necessary for promoting endothelial cell health under homeostatic conditions, predisposes to development of PH 29 . Finally, overexpression of Nudix hydrolase 1 (NUDT1), a detoxifying DNA enzyme, results in increased incorporation of oxidized nucleotides into DNA, promoting apoptosis resistance and proliferation secondary to DNA damage 30 ; NUDT1 inhibitors have been shown to block development of PH in the monocrotaline and sugen/hypoxia rat models.…”

Section: Dna Sensing and Its Role In Pulmonary Hypertensionmentioning

confidence: 99%

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

et al. 2021

View full text Add to dashboard Cite

For as long as nucleic acids have been utilized to vertically and horizontally transfer genetic ma-terial, living organisms have had to develop methods of recognizing cytosolic DNA as either pathogenic (microbial invasion) or physiologic (mitosis and cellular proliferation). Derangement in key signaling molecules involved in these pathways of nucleotide sensing result in a family of diseases labeled interferonopathies. An interferonopathy, characterized by constitutive expres-sion of type I interferons, ultimately manifests as severe autoimmune disease at a young age. Afflicted patients present with a constellation of immune-mediated conditions, including primary lung manifestations such as pulmonary fibrosis and pulmonary hypertension. The latter condi-tion is especially interesting in light of the known role that DNA damage plays in a variety of types of inherited and induced pulmonary hypertension, with free DNA detection elevated in the circula-tion of affected individuals. While little is known regarding the role of cytosolic DNA sensing in development of pulmonary vascular disease, exciting new research in the related fields of immu-nology and oncology potentially sheds light on future areas of fruitful exploration. As such, the goal of this review is to summarize the state of the field of nucleic acid sensing, extrapolating common shared pathways that parallel our knowledge of pulmonary hypertension, in a molecular and cell-specific manner. Principles of DNA sensing related to known pulmonary injury inducing stimuli are also evaluated, in addition to potential therapeutic targets. Finally, future directions in pulmonary hypertension research and treatments will be briefly discussed.

show abstract

Methyltransferase-Like 3–Driven N6-Methyladenosine Modification of RBPJ Promotes Vascular Remodeling in Pulmonary Hypertension

Du,

Zhang,

et al. 2024

The American Journal of Pathology

View full text Add to dashboard Cite

Oxidized DNA Precursors Cleanup by NUDT1 Contributes to Vascular Remodeling in Pulmonary Arterial Hypertension

Cited by 26 publications

References 51 publications

Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach

Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

Methyltransferase-Like 3–Driven N6-Methyladenosine Modification of RBPJ Promotes Vascular Remodeling in Pulmonary Hypertension

Contact Info

Product

Resources

About