Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism
ABSTRACT Female sex increases risk of Group I pulmonary arterial hypertension by roughly threefold, but the mechanism is unclear. Low expression of Cyp1b1, an enzyme that metabolizes estrogens, is associated with disease penetrance, particularly in women. We previously found that lower Pparγ levels...
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Wiley
2025-01-01
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| Series: | Pulmonary Circulation |
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| Online Access: | https://doi.org/10.1002/pul2.70054 |
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| author | Jingyuan Chen Xinping Chen Vineet Agrawal Christy S. Moore Tom Blackwell Nivedita Rathaur Santhi Gladson Anandharajan Rathinasabapathy Anna Hemnes Eric Austin James West |
| author_facet | Jingyuan Chen Xinping Chen Vineet Agrawal Christy S. Moore Tom Blackwell Nivedita Rathaur Santhi Gladson Anandharajan Rathinasabapathy Anna Hemnes Eric Austin James West |
| author_sort | Jingyuan Chen |
| collection | DOAJ |
| description | ABSTRACT Female sex increases risk of Group I pulmonary arterial hypertension by roughly threefold, but the mechanism is unclear. Low expression of Cyp1b1, an enzyme that metabolizes estrogens, is associated with disease penetrance, particularly in women. We previously found that lower Pparγ levels in murine PAH models, which may drive disease, are rescued by estrogen blockade. The goal of the current studies was to examine interaction of estrogen, Cyp1b1, and energy metabolism in cell culture and in knockout mice. We found that both estrogen and siRNA to Cyp1b1 resulted in reduction of Pparγ at a protein, but not transcript level, in addition to regulating Pparγ cofactors. siCyp1b1 reduced both basal and maximal respiration rates in a fatty acid oxidation Seahorse protocol. This Pparγ inhibition could be eliminated by blocking ubiquitination. RNA‐seq suggested that Cyp1b1 may be having important pulmonary hypertension effects both in concert with and independently of its effect on estrogen. Cyp1b1 knockout mice have lower Pparγ levels than WT mice both in normoxia and hypoxia, and develop mild pulmonary hypertension on a high fat diet. RNA‐seq on their lungs reflected similar pathways to those altered in endothelial cells alone – lipid metabolism, cytokines, and vasoreactivity‐associated genes, among others, but added genes associated with circadian rhythm. These data suggest multiple potential points for intervention in estrogen and Cyp1b1 mediated etiology of PAH, in particular Pparγ ubiquitination, but also suggests that both the difference between E2 and 16aOHE and the impact of Cyp1b1 is more complex than simply “degree of estrogenicity”. |
| format | Article |
| id | doaj-art-cfdfd2fc0ac344c39242fe4ad59f91cd |
| institution | DOAJ |
| issn | 2045-8940 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj-art-cfdfd2fc0ac344c39242fe4ad59f91cd2025-08-20T02:49:40ZengWileyPulmonary Circulation2045-89402025-01-01151n/an/a10.1002/pul2.70054Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent MechanismJingyuan Chen0Xinping Chen1Vineet Agrawal2Christy S. Moore3Tom Blackwell4Nivedita Rathaur5Santhi Gladson6Anandharajan Rathinasabapathy7Anna Hemnes8Eric Austin9James West10Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Cardiovascular Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Pediatrics Vanderbilt University Medical Center Nashville USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville Tennessee USAABSTRACT Female sex increases risk of Group I pulmonary arterial hypertension by roughly threefold, but the mechanism is unclear. Low expression of Cyp1b1, an enzyme that metabolizes estrogens, is associated with disease penetrance, particularly in women. We previously found that lower Pparγ levels in murine PAH models, which may drive disease, are rescued by estrogen blockade. The goal of the current studies was to examine interaction of estrogen, Cyp1b1, and energy metabolism in cell culture and in knockout mice. We found that both estrogen and siRNA to Cyp1b1 resulted in reduction of Pparγ at a protein, but not transcript level, in addition to regulating Pparγ cofactors. siCyp1b1 reduced both basal and maximal respiration rates in a fatty acid oxidation Seahorse protocol. This Pparγ inhibition could be eliminated by blocking ubiquitination. RNA‐seq suggested that Cyp1b1 may be having important pulmonary hypertension effects both in concert with and independently of its effect on estrogen. Cyp1b1 knockout mice have lower Pparγ levels than WT mice both in normoxia and hypoxia, and develop mild pulmonary hypertension on a high fat diet. RNA‐seq on their lungs reflected similar pathways to those altered in endothelial cells alone – lipid metabolism, cytokines, and vasoreactivity‐associated genes, among others, but added genes associated with circadian rhythm. These data suggest multiple potential points for intervention in estrogen and Cyp1b1 mediated etiology of PAH, in particular Pparγ ubiquitination, but also suggests that both the difference between E2 and 16aOHE and the impact of Cyp1b1 is more complex than simply “degree of estrogenicity”.https://doi.org/10.1002/pul2.70054Cyp1b1estrogenmetabolismPPargpulmonary hypertension |
| spellingShingle | Jingyuan Chen Xinping Chen Vineet Agrawal Christy S. Moore Tom Blackwell Nivedita Rathaur Santhi Gladson Anandharajan Rathinasabapathy Anna Hemnes Eric Austin James West Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism Pulmonary Circulation Cyp1b1 estrogen metabolism PParg pulmonary hypertension |
| title | Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism |
| title_full | Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism |
| title_fullStr | Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism |
| title_full_unstemmed | Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism |
| title_short | Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin‐Dependent Mechanism |
| title_sort | estrogen and cyp1b1 regulate pparγ in pulmonary hypertension through a ubiquitin dependent mechanism |
| topic | Cyp1b1 estrogen metabolism PParg pulmonary hypertension |
| url | https://doi.org/10.1002/pul2.70054 |
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