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

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 1

Reduced FXN and elevated CDKN2A expression in Group 1, 2, and 3 PH lungs.

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Reduced FXN and elevated CDKN2A expression in Group 1, 2, and 3 PH lungs...
(A) Representative images of lungs stained with immunofluorescent probes for Fxn (gray), CD31 (green), α-SMA (red), counterstained with DAPI (blue), and imaged by confocal microscopy. Scale bar: 50 μm. Quantification of Fxn colocalized within the CD31+ endothelium in rats treated with monocrotaline (MCT) (n = 6) or vehicle (n = 5). (B) Relative Cdkn2a expression by RT-qPCR in lung tissue from MCT-treated rats compared with vehicle control (n = 5/group). (C) Fxn mRNA expression in isolated CD31+ cells and (D) whole-lung CDKN2A mRNA levels in hypoxic interleukin-6 transgenic (IL6-Tg) (n = 3) versus normoxic WT mice (n = 5). (E) Fxn protein and (F) Cdkn2a transcript expression in lung tissue from ZSF1 obese rats treated with Sugen (SU5416) (Ob-Su) (n = 9) versus lean controls (n = 9–10). (G) Representative confocal images showing FXN (gray), CD31 (green), α-SMA (red), and counterstained with DAPI (blue). Scale bar: 50 μm. Quantification of FXN in the CD31+ endothelium of Group 1 PAH (n = 8) or Group 3 PH (n = 8) patient lungs compared with controls (No PH) (n = 6). (H) RT-qPCR of CDKN2A mRNA levels in lung tissue of patient without PH (n = 8), Group 1 (n = 11), or Group 3 PH (n = 12). Two-tailed Student’s t test (A–F) and 1-way ANOVA and Tukey’s post hoc analysis (G and H) with error bars that reflect mean ± SD.