TY - JOUR
T1 - Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
AU - Culley, Miranda K.
AU - Zhao, Jingsi
AU - Tai, Yi Yin
AU - Tang, Ying
AU - Perk, Dror
AU - Negi, Vinny
AU - Yu, Qiujun
AU - Woodcock, Chen Shan C.
AU - Handen, Adam
AU - Speyer, Gil
AU - Kim, Seungchan
AU - Lai, Yen Chun
AU - Satoh, Taijyu
AU - Watson, Annie M.M.
AU - Aaraj, Yassmin Al
AU - Sembrat, John
AU - Rojas, Mauricio
AU - Goncharov, Dmitry
AU - Goncharova, Elena A.
AU - Khan, Omar F.
AU - Anderson, Daniel G.
AU - Dahlman, James E.
AU - Gurkar, Aditi U.
AU - Lafyatis, Robert
AU - Fayyaz, Ahmed U.
AU - Redfield, Margaret M.
AU - Gladwin, Mark T.
AU - Rabinovitch, Marlene
AU - Gu, Mingxia
AU - Bertero, Thomas
AU - Chan, Stephen Y.
N1 - Funding Information:
Conflict of interest: SYC has served as a consultant for United Therapeutics. SYC is a director, officer, and shareholder in Synhale Therapeutics. SYC has held grants from Actelion and Pfizer. SYC and TB have filed patent applications regarding metabolism in pulmonary hypertension (US 10,925,869 B2, “Compositions and methods for treating pulmonary vascular disease” and WO 2015/171641 A1, “Coordinate control of pathogenic signaling by the MIR-130-301 family in pulmonary hypertension and fibroproliferative diseases”). Copyright: © 2021, American Society for Clinical Investigation. Submitted: January 21, 2020; Accepted: April 22, 2021; Published: June 1, 2021. Reference information: J Clin Invest. 2021;131(11):e136459. https://doi.org/10.1172/JCI136459.
Funding Information:
This work was supported by NIH grants F30 HL139017 (to MKC); R01 HL124021, HL122596, HL138437, and UH2/UH3 TR002073 (to SYC); American Heart Association Established Investigator Award 18EIA33900027 (to SYC); NIH K99HL135258 (to MG); NIH S10OD023684 (Instrument Grant); NIH R01 HL113178 and R01 HL130261 (to EAG); the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute; the United States Army Medical Research and Materiel Command?s Armed Forces Institute of Regenerative Medicine grant W81XWH-08-2-0034 (to OFK); and the French National Research Agency grant ANR-18-CE14-0025 (to TB). We thank J. Silberg (Rice University) for the GRX2 and GCN4 sensor plasmids. We thank W. Horne and the Health Sciences Sequencing Core (UPMC Children?s Hospital of Pittsburgh) for performing RNA sequencing. We thank the University of Pittsburgh Center for Biologic Imaging and the Mayo Clinic Cancer Center Pathology Research Core for technical help and use of their facilities and resources. We thank B. Van Houten for critical advice; R.M. Payne and H. Puccio for providing FXN flox/flox mice; R. Adams for providing Cdh5(PAC)-CreERT2 mice; and Y. Lu and S. Annis for technical support. We acknowledge the Center for Organ Recovery & Education, the organ donors, and their families for the human lung tissue samples used in this study.
Funding Information:
This work was supported by NIH grants F30 HL139017 (to MKC); R01 HL124021, HL122596, HL138437, and UH2/UH3 TR002073 (to SYC); American Heart Association Established Investigator Award 18EIA33900027 (to SYC); NIH K99 HL135258 (to MG); NIH S10OD023684 (Instrument Grant); NIH R01 HL113178 and R01 HL130261 (to EAG); the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute; the United States Army Medical Research and Materiel Command’s Armed Forces Institute of Regenerative Medicine grant W81XWH-08-2-0034 (to OFK); and the French National Research Agency grant ANR-18-CE14-0025 (to TB). We thank J. Silberg (Rice University) for the GRX2 and GCN4 sensor plasmids. We thank W. Horne and the Health Sciences Sequencing Core (UPMC Children’s Hospital of Pittsburgh) for performing RNA sequencing. We thank the University of Pittsburgh Center for Biologic Imaging and the Mayo Clinic Cancer Center Pathology Research Core for technical help and use of their facilities and resources. We thank B. Van Houten for critical advice; R.M. Payne and H. Puccio for providing FXN flox/flox mice; R. Adams for providing Cdh5(PAC)-CreERT2 mice; and Y. Lu and S. Annis for technical support. We acknowledge the Center for Organ Recovery & Education, the organ donors, and their families for the human lung tissue samples used in this study.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI136459
DO - 10.1172/JCI136459
M3 - Article
C2 - 33905372
AN - SCOPUS:85107207968
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
M1 - e136459
ER -