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Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase…

Overview of attention for article published in Circulation, September 2017
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (81st percentile)
  • Average Attention Score compared to outputs of the same age and source

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11 X users
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Title
Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis
Published in
Circulation, September 2017
DOI 10.1161/circulationaha.117.028069
Pubmed ID
Authors

Hui Zhang, Daren Wang, Min Li, Lydie Plecitá-Hlavatá, Angelo D'Alessandro, Jan Tauber, Suzette Riddle, Sushil Kumar, Amanda Flockton, B Alexandre McKeon, Maria G Frid, Julie A Reisz, Paola Caruso, Karim C El Kasmi, Petr Ježek, Nicholas W Morrell, Cheng-Jun Hu, Kurt R Stenmark

Abstract

Background -An emerging "metabolic theory" of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyper-proliferative, apoptosis-resistant, pro-inflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the TCA cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that, in PH-Fibs, miR-124 regulates polypyrimidine tract binding protein 1 (PTBP1) expression to control alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and PKM2) resulting in an increased PKM2/PKM1 ratio which promotes glycolysis and proliferation even in aerobic environments. Methods -Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects (CO-Fibs). PTBP1 gene knockdown was achieved via PTBP1-siRNA, restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and Shikonin were utilized to manipulate PKM2 glycolytic function. HDACi were used to treat cells. Metabolic products were determined by Mass spectrometry-based metabolomics analyses (UHPLC-MS), and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry. Results -We detected an increased PKM2/PKM1 ratio in PH-Fibs compared to CO-Fibs. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation and attenuated macrophage IL-1β expression. Further, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, i.e. lactate), rescued mitochondrial reprogramming and decreased cell proliferation. Pharmacological manipulation of PKM2 activity with TEPP-46 and Shikonin, or treatment with histone deacetylase inhibitors (HDACi), produced similar results. Conclusions -In PH, miR-124, through the alternative splicing factor PTBP1, regulates the PKM2/PKM1 ratio, the overall metabolic, proliferative and inflammatory state of cells. This PH phenotype can be rescued with interventions at various levels of the metabolic cascade. These findings suggest a more integrated view of vascular cell metabolism, which may open unique therapeutic prospects in targeting the dynamic glycolytic and mitochondrial interactions and between mesenchymal inflammatory cells in PH.

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X Demographics

The data shown below were collected from the profiles of 11 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 83 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 83 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 15 18%
Student > Bachelor 10 12%
Researcher 9 11%
Student > Master 8 10%
Student > Doctoral Student 7 8%
Other 14 17%
Unknown 20 24%
Readers by discipline Count As %
Medicine and Dentistry 19 23%
Biochemistry, Genetics and Molecular Biology 14 17%
Agricultural and Biological Sciences 10 12%
Nursing and Health Professions 5 6%
Engineering 3 4%
Other 7 8%
Unknown 25 30%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 December 2021.
All research outputs
#3,371,013
of 25,534,033 outputs
Outputs from Circulation
#6,320
of 21,157 outputs
Outputs of similar age
#59,450
of 328,977 outputs
Outputs of similar age from Circulation
#124
of 199 outputs
Altmetric has tracked 25,534,033 research outputs across all sources so far. Compared to these this one has done well and is in the 86th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 21,157 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 31.4. This one has gotten more attention than average, scoring higher than 70% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 328,977 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 81% of its contemporaries.
We're also able to compare this research output to 199 others from the same source and published within six weeks on either side of this one. This one is in the 38th percentile – i.e., 38% of its contemporaries scored the same or lower than it.