E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

Yi, Dan; Liu, Bin; Ding, Hongxu; Li, Shuai; Li, Rebecca; Pan, Jiakai; Ramirez, Karina; Xia, Xiaomei; Kala, Mrinalini; Ye, Qinmao; Lee, Won Hee; Frye, Richard E.; Wang, Ting; Zhao, Yutong; Knox, Kenneth S.; Glembotski, Christopher C.; Fallon, Michael B.; Dai, Zhiyu

doi:10.1161/hypertensionaha.123.21241

Cited by 4 publications

(7 citation statements)

References 50 publications

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“…In line with these results, autopsies from 4 out of 15 patients with PAH demonstrated marked decreases in SOX17 expression in pulmonary arterial endothelial cell (PAEC) (41). Recent studies have also shown decreased SOX17 gene expression and protein levels in pulmonary vascular endothelial cells (PVEC) isolated from PAH patients compared to failed donor lungs (34). Similarly, SOX17 silencing mutations in human PAECs result in increased apoptosis, proliferation and adhesion (41).…”

Section: Potential Pathogenic Mechanisms For Sox17 In Pahmentioning

confidence: 56%

“…SOX17 deficiency appears to upregulate endothelial cell hyperplasia and proliferation through upregulation of growth factor signaling in response to hypoxia or cellular stress. Interestingly, increased pulmonary vascular endothelial cell proliferation is observed in Sox17 deficient mice under hypoxic conditions (34). This appears to be due in part due to upregulation of Hepatocyte growth factor (HGF)/c-Met signaling.…”

Section: Potential Pathogenic Mechanisms For Sox17 In Pahmentioning

confidence: 99%

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Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension

Simmons Beck,

Liang,

Klinger

2023

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease.

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Section: Potential Pathogenic Mechanisms For Sox17 In Pahmentioning

confidence: 56%

Section: Potential Pathogenic Mechanisms For Sox17 In Pahmentioning

confidence: 99%

Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension

Simmons Beck,

Liang,

Klinger

2023

Front. Cardiovasc. Med.

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“…BMI1 [245], CCL5 [246], GREM1 [247], ANGPTL3 [248], ARG2 [249], MSRA (methionine sulfoxidereductase A) [250], SNCA (synuclein alpha) [251], NOX4 [252], PFKFB2 [253], PDZK1 [254], SUCNR1 [255], LYVE1 [256], AZGP1 [257], ERBB4 [258] and PLAT (plasminogen activator, tissue type) [259] might serve as molecular markers for kidney fibrosis. BMI1 [260], IGF2 [261], IRF7 [262], CCL5 [263], ACTN3 [264], E2F1 [265], PF4 [266], TEAD4 [267], TBX4 [268], GREM1 [269], CYP11B2 [270], WNT3A [124], COMP (cartilage oligomeric matrix protein) [271], FLI1 [272], RAP1B [273], ANGPTL3 [274], CYP3A5 [275], HSD11B2 [276], HMGCS2 [277], AGXT2 [278], SLC22A12 [279], FGF1 [280], CRY1 [281], PPARGC1A [282], SLC19A3 [283], CYP2C8 [284], ACOX2 [285], SLC2A9 [286], MSRA (methionine sulfoxidereductase A) [287], VNN1 [288], EPHX2 [289], CROT (carnitine O-octanoyltransferase) [290], SCNN1B [291], NR4A3 [292], HSD17B7 [293], SLC22A2 [294], AQP2 [295], SLC2A2 [296], EGF (epidermal growth factor) [297], ANGPT1 [298], SLC26A4 [299], KL (klotho) [300], SCNN1G [301], PDZK1 [302], PTPRD (protein tyrosine phosphatase receptor type D) [303], ACE2 [304], FOLH1 [305], SUCNR1 [306], GLCE (glucuronic acid epimerase) [307], AQP3 [308], DPP4 [309], REN (renin) [310], TRPM6 [311], ABCB1 [312], MTTP (microsomal triglyceride transfer protein) [313], CALCRL (calcitonin receptor like receptor) [314], ENPEP (glutamylaminopept...…”

Section: Discussionmentioning

confidence: 99%

“…E2F1 [110], BMI1 [95], EEF1A2 [104], ACTA1 [128], VCAM1 [220], AGTR1 [58], hsa-mir-221 [784], MEF2A [785], FOXC1 [786], YY1 [787], STAT3 [788] and BRCA1 [789] were significantly associated with cardiovascular disorders. E2F1 [265], BMI1 [260], VCAM1 [321], AGTR1 [64], hsa-mir-638 [790], hsa-mir-221 [791], FOXC1 [792], YY1 [793], STAT3 [794] and BRCA1 [795] provided a clear picture of the prognosis of patients with hypertension. E2F1 [329], BMI1 [327], VCAM1 [376], USF2 [796], YY1 [797], STAT3 [798] and BRCA1 [799] have always been found in AKI.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Vastrad,

Vastrad

2024

Preprint

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Acute kidney injury (AKI) is a type of renal disease occurs frequently in hospitalized patients, which may cause abnormal renal function and structure with increase in serum creatinine level with or without reduced urine output. With the incidence of AKI is increasing. However, the molecular mechanisms of AKI have not been elucidated. It is significant to further explore the molecular mechanisms of AKI. We downloaded the GSE139061 next generation sequencing (NGS) dataset from the Gene Expression Omnibus (GEO) database. Limma R bioconductor package was used to screen the differentially expressed genes (DEGs). Then, the enrichment analysis of DEGs in Gene Ontology (GO) function and REACTOME pathways was analyzed by g:Profiler. Next, the protein-protein interaction (PPI) network and modules was constructed and analyzed, and the hub genes were identified. Next, the miRNA-hub gene regulatory network and TF-hub gene regulatory network were built. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. Overall, 956 DEGs were identified, including 478 up regulated and 478 down regulated genes. The enrichment functions and pathways of DEGs involve primary metabolic process, small molecule metabolic process, striated muscle contraction and metabolism. Topological analysis of the PPI network and module revealed that hub genes, including PPP1CC, RPS2, MDFI, BMI1, RPL23A, VCAM1, ALB, SNCA, DPP4 and RPL26L1, might be involved in the development of AKI. miRNA-hub gene and TF-hub gene regulatory networks revealed that miRNAs and TFs including hsa-mir-510-3p, hsa-mir-6086 and mir-146a-5p, MAX and PAX2, might be involved in the development of AKI. Various known and newtherapeutic targets were obtained via network analysis. The results of the current investigation might be beneficial for the diagnosis and treatment of AKI.

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“…Downregulation of SOX17 in pulmonary artery ECs (PAECs) increases susceptibility to PAH, particularly with exposure to hypoxia ( 75 , 76 ). Notably, mice with EC-specific SOX17 deletion developed spontaneous, mild PH and exacerbated hypoxia-induced PH ( 77 ). Upregulation in SOX17 can also attenuate PAH via inhibition of HIF2α ( 78 ).…”

Section: Mutations Regulating Endothelial Functionmentioning

confidence: 99%

Endothelial cell clonality, heterogeneity and dysfunction in pulmonary arterial hypertension

Newcomb,

Farkas

2023

Front. Med.

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Our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) has evolved over recent years, with the recognition that endothelial cell (EC) dysfunction and inflammation play an integral role in the development of this disease. ECs within the pulmonary vasculature play a unique role in maintaining vascular integrity and barrier function, regulating gas exchange, and contributing to vascular tone. Using single-cell transcriptomics, research has shown that there are multiple, unique EC subpopulations with different phenotypes. In response to injury or certain stressors such as hypoxia, there can be a dysregulated response with aberrant endothelial injury repair involving other pulmonary vascular cells and even immune cells. This aberrant signaling cascade is potentially a primary driver of pulmonary arterial remodeling in PAH. Recent studies have examined the role of EC clonal expansion, immune dysregulation, and genetic mutations in the pathogenesis of PAH. This review summarizes the existing literature on EC subpopulations and the intricate mechanisms through which ECs develop aberrant physiologic phenotypes and contribute to PAH. Our goal is to provide a framework for understanding the unique pulmonary EC biology and pathophysiology that is involved in the development of PAH.

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E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

Cited by 4 publications

References 50 publications

Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension

Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

Endothelial cell clonality, heterogeneity and dysfunction in pulmonary arterial hypertension

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