Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1177875 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31122439_1.fastq.gz | Fastqsanger.gz | |||
| SRR31122439_2.fastq.gz | Fastqsanger.gz | |||
| SRR31122440_1.fastq.gz | Fastqsanger.gz | |||
| SRR31122440_2.fastq.gz | Fastqsanger.gz | |||
| SRR31122441_1.fastq.gz | Fastqsanger.gz |
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Project description:Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension [bulk RNA-seq]
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Project description:SRY-Box Transcription Factor 17 (SOX17) enhancers variants and mutations are found in patients with pulmonary arterial hypertension (PAH). In human PAH pulmonary microvascular endothelial cells (HPMVEC), there is a significant downregulation of SOX17 expression. We hypothesized that SOX17 deficiency contributes to the pathogenesis of PAH and found that mice with endothelial specific disruption (ecKO Sox17) developed spontaneous pulmonary hypertension (PH) and exacerbated hypoxia-induced PH. Loss of SOX17 in lung ECs induces cell cycle programming, proliferative and anti-apoptotic phenotypes, a process mediated by the activation of E2F Transcription Factor 1 (E2F1) signaling. Pharmacological inhibition of E2F1 in ecKO Sox17 mice attenuated PH and cell cycle programming. Our study demonstrated that endothelial SOX17 deficiency induces PH and targeting E2F1 signaling represents a promising approach in PAH patients.
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Project description:FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression is protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 deficiency impaired basal mitophagy in endothelial cells, leading to accumulation of dysfunctional mitochondria, metabolic reprogramming towards aerobic glycolysis, pseudohypoxia and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, Fundc1-deficient endothelial cells increased IGFBP2 secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence or IGFBP2. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells .
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