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Implication of EZH2 in the hyper-proliferative and apoptosis-resistant phenotype of pulmonary artery smooth muscle cells in PAH: a transcriptomic and proteomic approach

ABSTRACT: The aim of this study was to determine whether EZH2 represents a new factor critically involved in the cancer-like 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 TCA 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166996 | GEO | 2021/04/14

REPOSITORIES: GEO

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Pharmacological inhibition of G9a ameliorates pulmonary vascular remodeling in PAH

Project description:Background:Pulmonary arterial hypertension (PAH) is a severe condition characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a has been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that G9a up-regulation in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. Methods: G9alevels were measured in PAs and isolated PASMCs of PAH patients and animal models. Selective G9a pharmacological inhibitors were used in human PAH-PASMCs and in rodent PAH models (i.e.Fawn-Hooded rats and Sugen/Hypoxia-exposed mice). Results: We present evidence of increased expression of G9a in PASMCs from PAH patients as well as in remodeled PAs from animal models. We found that pharmacological inhibition of G9a activity using BIX01294 and UNC0642significantly reduces the prosurvival and proproliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in Fawn-Hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. Conclusions:These findings suggest that G9a inhibition may represent a new therapeutic approach in PAH.

2023-01-20 | GSE200821 | GEO

Revealing the target of PASMC from PAH patients and mechanism

Project description:The goal of this study is to identify the target of PAH in PASMC from donor control and PAH patients by transcriptome profiling (RNA-seq) and the mechanism from transcriptome profiling (RNA-seq) and histone modification (ChIPseq)

2021-07-28 | GSE168905 | GEO

Differential Gene Expression Profiles of PASMCs Induced by Quercetin under Hypoxia

Project description:As the critical step of pathogenesis during hypoxic pulmonary arterial hypertension (PAH) vascular remodeling is closely associated with pulmonary arterial smooth muscle cell (PASMC) alterations induced by hypoxia that include persistent vasoconstriction, abnormal proliferation and PASMC resistance to apoptosis. Quercetin is a flavonoid compound extracted from green plants that inhibits proliferation, induces apoptosis, arrests the cell cycle, and rescues the constriction of PASMCs, but the underlying mechanisms remain poorly understood. In this study, we used a commercial Agilent Whole Rat Genome Oligo Microarray to determine the overall transcriptional response of PASMCs in response to exposure to hypoxia and the optimal concentration of quercetin. Hypoxia induced the upregulation of 1694 genes and the downregulation of 2091 genes compared with the normoxia group. Quercetin treatment resulted in 1790 upregulated genes and 1450 downregulated genes. Quercetin is known to cause differential expression of several of these genes that are known to promote proliferation, induce apoptosis (Cycs, Ppp3ca, Prkar2b, Akt3, Ppp3cc, Il1rap, Ntrk1), arrest the cell cycle (Chek2, Cdkn1c, Gadd45b, Stag2, Anapc7, Orc1, Ccne1, Myc3, Skp1, Espl1, Cdc45, Mcm4), and rescue PASMC constriction (Ramp1, Ramp3, Adcy5, Gnas, Prkcd, Itpr3, Adra1d, Calm1, Npr1, Avpr1a, Ednra, Adcy8). Real-time quantitative RT-PCR was performed to verify the microarray results. In conclusion, quercetin altered the expression profile of many genes regulated by hypoxia in PASMCs, which helps to further explore the mechanism of the effects of quercetin treatment on hypoxic PAH.

2015-08-20 | GSE72181 | GEO

A critical role of microRNAs in human pulmonary arterial hypertension. miR-204: a novel therapeutic target (gene expression)

Project description:Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. Downregulation of the BMPR2 gene along with activation of the transcription factor NFAT have been implicated in the maintenance of pro-proliferative and anti-apoptotic stages of cells. Since an increasing number of microRNAs have been implicated in the regulation of genes specifically important for cell proliferation and apoptosis, we hypothesized that microRNAs might be associated with these cellular features in the etiology of PAH. We demonstrate that downregulation of one such microRNA (miR-204) in human PAH-PASMC promotes the activation of an Src/STAT3/NFAT axis that increases PAH-PASMC proliferation and their resistance to apoptosis. Stimulation experiments using the pro-PAH factors (PDGF, endothelin-1 and angiotensin II) and time course analysis in experimental PAH show that STAT3 activation leads to miR-204 downregulation, thereby activating an Src-dependent positive feedback loop sustaining STAT3 and activating NFAT. More importantly, restoring miR-204 expression decreases proliferation and resistance to apoptosis in human and in an experimental PAH model. Taken together, our study uncovers a new STAT3-miR-204-Src/STAT3/NFAT axis that links the STAT3-dependent downregulation of BMPR2 with the NFAT-mediated pro-proliferative and anti-apoptotic phenotype observed in PAH. Our data point toward a novel potential strategy for treating patients with PAH. Comparative expression profiling of PAH versus healthy patients to evaluate the modulated genes in the disease. Following the demonstration of the downregulation of miR-204 in PAH we want to investigate the effect of the inhibition (using antagomir) of miR-204 expression in PASMC cells.

2010-12-16 | E-GEOD-21280 | biostudies-arrayexpress

A critical role of microRNAs in human pulmonary arterial hypertension. miR-204: a novel therapeutic target (TaqMan qPCR)

2010-12-16 | E-GEOD-21281 | biostudies-arrayexpress

Revealing the target of PASMC from PAH patients and mechanism

Project description:Revealing the target of PASMC from PAH patients and mechanism

| PRJNA714539 | ENA

Comprehensive transcriptome analysis of the heart in control, PAH and PAH/aKO mice.

Project description:Pregnancy-associated hypertensive (PAH) mice were maintained by mating females carrying the human angiotensinogen (hAGT) gene with males expressing the human renin (hRN) gene, as previously described (Takimoto E., et al., Science, 1996). Angiotensin II (AngII) has critical roles in regulation of blood pressure. In late pregnancy of PAH mice, increased AngII causes acute and severe hypertension with proteinuria. Furthermore, PAH mice show cardiac hypertrophy, fibrosis and apoptosis. It is known that AngII downregulates mRNA of alpha 1a-adrenergic receptor (Adra1a) in neonatal rat cardiac myocytes (Li H.T., et al., Circ. Res., 1997). Interestingly, we found that Adra1a knock out PAH (PAH/aKO) mice display more severe phenotype of cardiac hypertrophy in comparison to PAH mice. In this study, to understand the molecular basis of cardiac hypertrophy via regulation of Adra1a expression with AngII in PAH mice, we performed a comprehensive analysis of gene expression changes in cardiac remodeling of PAH and PAH/aKO mice using the next-generation RNA sequencing (RNA-seq).

2023-01-27 | GSE140948 | GEO

A critical role of microRNAs in human pulmonary arterial hypertension. miR-204: a novel therapeutic target (TaqMan qPCR)

2010-12-16 | GSE21281 | GEO

A critical role of microRNAs in human pulmonary arterial hypertension. miR-204: a novel therapeutic target (gene expression)

2010-12-16 | GSE21280 | GEO

Epigenetic dysregulation of the Drp1 binding partners MiD49 and MiD51 increases mitotic mitochondrial fission and promotes pulmonary arterial hypertension: mechanism and therapeutic implications

Project description:Mitotic fission is increased in hyperproliferative, apoptosis-resistant diseases, such as pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype includes activation of the fission mediator, dynamin related protein 1 (Drp1), which must complex with its adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore the role of their dysregulation in the pathogenesis of PAH. MiDs are increased in PAH PASMC. This accelerates Drp1-mediated mitotic fission, which increases cell proliferation and decreases apoptosis. Silencing MiDs (but not Fis1 or MFF) promotes mitochondrial fusion and G1-phase cell cycle arrest through an ERK1/2 and CDK4-dependent mechanism. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased microRNA-34a-3p (miR-34a-3p) expression. Circulatory miR34a-3p expression is decreased in PAH patients as well as in preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. We used microarrays to identify differences in miR expression in pulmonary artery smooth muscle cells (PASMC) taken from either pulmonary arterial hypertension patients or healthy controls

2018-01-31 | GSE108707 | GEO

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