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Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
The Journal of clinical investigation, 2021-06, Vol.131 (11), p.1-17
2021
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Autor(en) / Beteiligte
Titel
Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
Ist Teil von
  • The Journal of clinical investigation, 2021-06, Vol.131 (11), p.1-17
Ort / Verlag
United States: American Society for Clinical Investigation
Erscheinungsjahr
2021
Quelle
MEDLINE
Beschreibungen/Notizen
  • The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich's ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
Sprache
Englisch
Identifikatoren
ISSN: 1558-8238, 0021-9738
eISSN: 1558-8238
DOI: 10.1172/JCI136459
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8159699
Format
–
Schlagworte
Animals, Apoptosis, Ataxia, Biomedical research, Biosynthesis, Cardiomyopathy, Cardiovascular disease, Cellular Senescence - genetics, Development and progression, DNA biosynthesis, DNA damage, Drug development, Ejection fraction, Endothelial cells, Endothelial Progenitor Cells - metabolism, Endothelial Progenitor Cells - pathology, Endothelium, Endothelium, Vascular - metabolism, Endothelium, Vascular - pathology, Etiology, Female, Frataxin, Friedreich Ataxia - genetics, Friedreich Ataxia - metabolism, Friedreich Ataxia - pathology, Friedreich's ataxia, Health aspects, Heart diseases, Heart failure, Humans, Hypertension, Hypertension, Pulmonary - genetics, Hypertension, Pulmonary - metabolism, Hypertension, Pulmonary - pathology, Hypoxia, Inflammation, Iron deficiency, Iron in the body, Iron-Binding Proteins - genetics, Iron-Binding Proteins - metabolism, Lung diseases, Lungs, Male, Medical research, Medicine, Experimental, Metabolism, Mice, Mice, Knockout, Mitochondria, Molecular chaperones, Mutation, Nutrient deficiency, Patients, Physiological aspects, Pulmonary hypertension, Senescence, Shunts, Smooth muscle, Stem cells, Sulfur, Sulfur compounds, Transgenic animals, Vascular Remodeling - genetics

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