Snhg18 promotes hypoxic pulmonary hypertension by enhancing glycolysis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305837 | GEO | 2026/05/01
REPOSITORIES: GEO
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Project description:Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes the conversion of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA), which is critical to prevent auto-inflammatory responses mediated by activation of the type I interferon (IFN) signaling. Here, we define the role of ADAR1-dependent RNA editing in interferon-β(IFNβ) activation and pulmonary artery smooth muscle cell (PASMC) remodeling in pulmonary arterial hypertension (PAH), a devastating disease leading to right heart failure and premature death. Methods: RNA editing levels were analyzed in human pulmonary artery smooth muscle cells (PASMCs) from idiopathic PAH (IPAH) patients versus healthy controls. A conditional transgenic line ADAR1SMC-KO was generated by knocking out ADAR1 selectively in α-smooth muscle actin-positive cells, followed by hypoxic exposure to induce PH. Results: PASMCs from IPAH patients displayed decreased levels of ADAR1 mRNA and protein, accompanied by reduced A-to-I editing compared to healthy PASMCs. ADAR1 knockdown in PASMCs upregulated MDA5, PKR, IFN-β and IFN-Stimulated Genes (ISGs). Compared with controls in vivo, hypoxic ADAR1SMC-KO mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles and increased vascular leakage resulting in elevated right ventricular systolic pressure and right ventricular hypertrophy. Mechanistically, IFNβ signaling in ADAR1SMC-KO lungs induced the recruitment of inflammatory cells, including macrophages, which in turn enhanced PASMC proliferation and muscularization. Correspondingly, pharmacological treatment with PKR kinase inhibitor Imoxin decreased IFNβ thus attenuating the hypoxia-induced PH phenotype of ADAR1SMC-KO mice. Conclusions: ADAR1-dependent A-to-I RNA editing tempers IFN signaling in PASMCs. Pathologic reduction of ADAR1 in SMCs increased IFNβ activity, macrophage recruitment, and worsened PH, thus demonstrating a direct detrimental role of vascular innate immune responses in PH. Targeting PKR could be the new therapeutic strategy aimed at treating PAH.
2025-09-03 | GSE228134 | GEO
Project description:Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes the conversion of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA), which is critical to prevent auto-inflammatory responses mediated by activation of the type I interferon (IFN) signaling. Here, we define the role of ADAR1-dependent RNA editing in interferon-β(IFNβ) activation and pulmonary artery smooth muscle cell (PASMC) remodeling in pulmonary arterial hypertension (PAH), a devastating disease leading to right heart failure and premature death. Methods: RNA editing levels were analyzed in human pulmonary artery smooth muscle cells (PASMCs) from idiopathic PAH (IPAH) patients versus healthy controls. A conditional transgenic line ADAR1SMC-KO was generated by knocking out ADAR1 selectively in α-smooth muscle actin-positive cells, followed by hypoxic exposure to induce PH. Results: PASMCs from IPAH patients displayed decreased levels of ADAR1 mRNA and protein, accompanied by reduced A-to-I editing compared to healthy PASMCs. ADAR1 knockdown in PASMCs upregulated MDA5, PKR, IFN-β and IFN-Stimulated Genes (ISGs). Compared with controls in vivo, hypoxic ADAR1SMC-KO mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles and increased vascular leakage resulting in elevated right ventricular systolic pressure and right ventricular hypertrophy. Mechanistically, IFNβ signaling in ADAR1SMC-KO lungs induced the recruitment of inflammatory cells, including macrophages, which in turn enhanced PASMC proliferation and muscularization. Correspondingly, pharmacological treatment with PKR kinase inhibitor Imoxin decreased IFNβ thus attenuating the hypoxia-induced PH phenotype of ADAR1SMC-KO mice. Conclusions: ADAR1-dependent A-to-I RNA editing tempers IFN signaling in PASMCs. Pathologic reduction of ADAR1 in SMCs increased IFNβ activity, macrophage recruitment, and worsened PH, thus demonstrating a direct detrimental role of vascular innate immune responses in PH. Targeting PKR could be the new therapeutic strategy aimed at treating PAH.
2025-09-03 | GSE228133 | GEO
Project description:BACKGROUND: Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary vascular remodeling, primarily driven by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). While non-coding RNAs such as circular RNAs have been implicated in PH, the role of tRNA-derived small RNA (tsRNA) remains poorly understood. Among them, i-tRF-Asp represents a novel tsRNA whose function in hypoxic PH is unknown. This study aims to investigate whether i-tRF-Asp contributes to PASMC proliferation and vascular remodeling in hypoxic PH. METHODS: To elucidate the functional role of i-tRF-Asp, loss-of-function experiments were conducted in vitro using hypoxic mouse PASMCs (mPASMCs), alongside in vivo studies utilizing both SuHx (Sugen5416+hypoxia) induced pulmonary hypertension models in both adult male C57BL/6 mice and Sprague-Dawley rats. These models employed antisense oligonucleotide inhibitor and adeno-associated virus-mediated silencing. The underlying mechanisms were further explored via RNA immunoprecipitation, liquid-liquid phase separation assays, cell proliferation assessment, western blot, alternative splicing profiling and molecular dynamics simulation. RESULTS: Inhibition of i-tRF-Asp ameliorated hypoxia-induced pulmonary vascular remodeling, primarily through suppressing excessive proliferation of mPASMCs. Further analysis indicated that i-tRF-Asp facilitates liquid–liquid phase separation (LLPS) of hnRNPU. This process mediates selective recruitment of Tcf7l2 pre-mRNA and promotes alternative splicing, resulting in a pro-proliferative Tcf7l2 transcript variant that drives mPASMC proliferation. Furthermore, we have identified that the endonuclease ERN1 can upregulate the expression of i-tRF-Asp. CONCLUSION: The endoribonuclease ERN1 upregulates the expression of i-tRF-Asp, which in turn facilitates mPASMC proliferation and pulmonary vascular remodeling. This process is driven by hnRNPU LLPS-dependent alternative splicing of the long Tcf7l2 transcript isoform.
2026-06-03 | GSE328570 | GEO
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
Project description:To illuminate new actionable targets involved in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), we performed RNA sequencing on pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients and control donors. We then enriched our own experiment with publicly available datasets. Aggregation of gene expression datasets followed by functional enrichment and connectivity map analyses on common upregulated genes in PAH-PASMCs revealed Aurora kinase B (AURKB), the enzymatic core of the chromosomal passenger complex with BIRC5, as a potential driver and therapeutic target in PAH. Using pharmacological and molecular tools, we demonstrated that inhibition of AURKB in PAH-PASMCs blocks cell cycle progression, induces cell death, and reverses the gene signature of PAH-PASMCs. In addition, we provided evidence that AURKBi-treated PAH-PASMCs that escape apoptosis, acquire a senescence-associated secretory phenotype. In vivo, AURKB inhibition using Barasertib significantly improved hemodynamics in two preclinical models of established PAH by attenuating pulmonary vascular remodeling. A therapeutic effect was also observed in precision-cut lung slices generated from human lungs, thus confirming the predictive value of AURKB interference as a potential therapeutic for PAH progression.Finally, we demonstrated that the combination of Barasertib with the anti-senescent agent UC2288 was more effective in reducing vascular remodeling than either drug alone.
2024-11-28 | GSE263226 | GEO
Project description:Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by non-resolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent anti-proliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the anti-proliferative effect of MRE-269. ID signaling may be involved in the anti-proliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the anti-proliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.
2022-12-27 | GSE221511 | GEO
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. The levels of senescence marker, p16INK4A and senescence-associated β-galactosidase (SA-β-gal) activity are higher in PA endothelial cells (ECs) isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16fl/fl-Cdh5(PAC)-CreERT2 (p16iΔEC) mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing platelet-derived growth factor (PDGFB) expression. Transcriptomic analyses of IPAH patient or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and their interaction with TWIST1. Knockdown of p16INK4A attenuates the expression of PDGFB and TWIST1 in IPAH patient PAECs or hypoxia-treated mouse lungs and suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel implanted on the mouse lungs. Hypoxia-treated mouse lung EC-derived exosomes stimulate DNA synthesis and migration of PASMCs in vitro and in the gel implanted on the mouse lungs, while p16iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-15 | PXD033549 | Pride
Project description:Background: The phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling, contributing to pulmonary hypertension (PH). Super-enhancers (SEs) are characterized by histone modifications and the binding of coactivators, which drive the expression of prominent genes which define cellular identity. The specific role of SEs, especially SE-driven long non-coding RNAs (lncRNAs), in hypoxia-induced phenotypic plasticity of PASMCs remains unclear. Methods: In this study, the lncRNA UNC5B-AS1 regulated by SEs was screened in hypoxic PASMCs using RNA sequencing and H3K27ac chromatin immunoprecipitation (ChIP) sequencing. Overexpression or knockdown of UNC5B-AS1 in vitro was performed to elucidate its role in PH pathogenesis. A serotype 5 adenovirus-associated virus carrying a conserved functional fragment of UNC5B-AS1 was used to treat PH in vivo. Results: We identified UNC5B-AS1 as an SE-driven lncRNA transcriptionally activated by the transcription factor FOXP3, which regulates phenotypic transition in PASMCs. Notably, we demonstrated that UNC5B-AS1 interacts with key glycolytic enzymes in the cytoplasm, and likely serves as a molecular scaffold for Leucine-Rich PPR Motif-Containing Protein (LRPPRC) and oxidative respiratory chain complex IV in the mitochondria. Consequently, the deficiency of UNC5B-AS1 in PASMCs promotes the lactylation of promoter regions within inflammatory genes, including those of IL-1β, IL-6, and TNF-α, under hypoxic conditions, ultimately leading to phenotypic transition of PASMCs. Conclusions: Our findings identify SE-driven UNC5B-AS1 as a novel regulatory factor in the hypoxia-induced phenotypic transition of PASMCs and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for PH.
2025-05-01 | GSE288999 | GEO
Project description:Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH is caused, among other factors, by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMC) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVEC). Upon re-exposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, we aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature.
2022-09-01 | GSE183908 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that culminates in right heart failure. Vascular pathology in PH is characterized by pulmonary vasoconstriction and progressive vascular remodeling processes that affects all layers of the vascular wall (intima, media and adventitia).
2022-06-09 | GSE194080 | GEO