ELIZA

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501283 occurrences (No.27 in the rank) during 5 years in the PubMed. [cache]

262) Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs.

--- ABSTRACT ---

PMID:33565360 DOI:10.1152/ajplung.00407.2020

2021 American journal of physiology. Lung cellular and molecular physiology

* Matrix stiffening induces a pathogenic QKI-miR-7-SRSF1 signaling axis in pulmonary arterial endothelial cells.

- Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA-binding protein quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness upregulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine-rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally upregulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from patients with PAH and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, whereas forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

--- ABSTRACT END ---

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--- WordNet output for levels --- Overview of noun level The noun level has 8 senses (first 6 from tagged texts) 1. (69) degree, grade, level -- (a position on a scale of intensity or amount or quality; "a moderate grade of intelligence"; "a high level of care is required"; "it is all a matter of degree") 2. (22) grade, level, tier -- (a relative position or degree of value in a graded group; "lumber of the highest grade") 3. (15) degree, level, stage, point -- (a specific identifiable position in a continuum or series or especially in a process; "a remarkable degree of frankness"; "at what stage are the social sciences?") 4. (5) level -- (height above ground; "the water reached ankle level"; "the pictures were at the same level") 5. (1) level, spirit level -- (indicator that establishes the horizontal when a bubble is centered in a tube of liquid) 6. (1) horizontal surface, level -- (a flat surface at right angles to a plumb line; "park the car on the level") 7. level, layer, stratum -- (an abstract place usually conceived as having depth; "a good actor communicates on several levels"; "a simile has at least two layers of meaning"; "the mind functions on many strata simultaneously") 8. floor, level, storey, story -- (a structure consisting of a room or set of rooms at a single position along a vertical scale; "what level is the office on?") Overview of verb level The verb level has 6 senses (first 3 from tagged texts) 1. (4) level -- (aim at; "level criticism or charges at somebody") 2. (1) level, raze, rase, dismantle, tear down, take down, pull down -- (tear down so as to make flat with the ground; "The building was levelled") 3. (1) flush, level, even out, even -- (make level or straight; "level the ground") 4. charge, level, point -- (direct into a position for use; "point a gun"; "He charged his weapon at me") 5. level -- (talk frankly with; lay it on the line; "I have to level with you") 6. level, level off -- (become level or even; "The ground levelled off") --- WordNet end ---