Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
Miranda K. Culley, … , Thomas Bertero, Stephen Y. Chan
Miranda K. Culley, … , Thomas Bertero, Stephen Y. Chan
Published April 27, 2021
Citation Information: J Clin Invest. 2021;131(11):e136459. https://doi.org/10.1172/JCI136459.
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Research Article Pulmonology Vascular biology Article has an altmetric score of 24

Frataxin deficiency promotes endothelial senescence in pulmonary hypertension

Abstract

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.

Authors

Miranda K. Culley, Jingsi Zhao, Yi Yin Tai, Ying Tang, Dror Perk, Vinny Negi, Qiujun Yu, Chen-Shan C. Woodcock, Adam Handen, Gil Speyer, Seungchan Kim, Yen-Chun Lai, Taijyu Satoh, Annie M.M. Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Dmitry Goncharov, Elena A. Goncharova, Omar F. Khan, Daniel G. Anderson, James E. Dahlman, Aditi U. Gurkar, Robert Lafyatis, Ahmed U. Fayyaz, Margaret M. Redfield, Mark T. Gladwin, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y. Chan

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Figure 2

A subpopulation of FXN-deficient senescent cells in the endothelium of patients with PAH.

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A subpopulation of FXN-deficient senescent cells in the endothelium of p...
(A and B) Immunoblot of FXN and p16INKA levels in cultured pulmonary microvascular endothelial cells (PMVECs) from a healthy patient versus a Group 1 patient with PAH (n = 3/group). (C) Representative brightfield images (scale bar: 400 μm) and quantification of the percentage of SA-β-gal–positive PMVECs (blue) from a healthy patient versus a Group 1 patient with PAH. (D) From single-cell RNA sequencing of lungs from Group 1 patients with PAH (n = 3) versus no PAH control (n = 4), aggregate UMAP plots were generated of all endothelial cells in each cohort. Single-positive (CDKN2A, green or MKI67, orange), double-positive (blue), and double-negative (gray) endothelial cells are marked, along with total percentages across the aggregate cohort populations. (E) Percentages of CDKN2A-positive and MKI67-positive endothelial cells in each individual patient were compared between cohorts (PAH vs. no PAH). (F) Aggregate UMAP plot of pulmonary endothelial cells across all sampled patients (n = 7), demonstrating the percentage of single-positive (CDKN2A-expressing, green or high FXN-expressing, orange), double-positive (CDKN2A-expressing and high FXN expressing, blue), and double-negative (CDKN2A-expressing and non–high FXN expressing, gray) cells. Two-tailed Student’s t test with error bars that reflect mean ± SD.