S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia
Background Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S‐nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. Methods and Results Here, we s...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-03-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.024008 |
| _version_ | 1827907350961324032 |
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| author | Shathiyah Kulandavelu Raul A. Dulce Christopher I. Murray Michael A. Bellio Julia Fritsch Rosemeire Kanashiro‐Takeuchi Himanshu Arora Ellena Paulino Daniel Soetkamp Wayne Balkan Jenny E. Van Eyk Joshua M. Hare |
| author_facet | Shathiyah Kulandavelu Raul A. Dulce Christopher I. Murray Michael A. Bellio Julia Fritsch Rosemeire Kanashiro‐Takeuchi Himanshu Arora Ellena Paulino Daniel Soetkamp Wayne Balkan Jenny E. Van Eyk Joshua M. Hare |
| author_sort | Shathiyah Kulandavelu |
| collection | DOAJ |
| description | Background Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S‐nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. Methods and Results Here, we show that mice lacking S‐nitrosoglutathione reductase (GSNOR−⁄−), a denitrosylase regulating protein S‐nitrosylation, exhibit a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation. Reactive oxygen species, NO, and peroxynitrite levels are elevated. Importantly, mass spectrometry reveals elevated placental S‐nitrosylated amino acid residues in GSNOR−⁄− mice. Ascorbate reverses the phenotype except for fetal weight, reduces the difference in the S‐nitrosoproteome, and identifies a unique set of S‐nitrosylated proteins in GSNOR−⁄− mice. Importantly, human preeclamptic placentas exhibit decreased GSNOR activity and increased nitrosative stress. Conclusions Therefore, deficiency of GSNOR creates dysregulation of placental S‐nitrosylation and preeclampsia in mice, which can be rescued by ascorbate. Coupled with similar findings in human placentas, these findings offer valuable insights and therapeutic implications for preeclampsia. |
| first_indexed | 2024-03-13T01:07:54Z |
| format | Article |
| id | doaj.art-7c58d4a5e22d48efa2ccc96e5a6e59bc |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-13T01:07:54Z |
| publishDate | 2022-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-7c58d4a5e22d48efa2ccc96e5a6e59bc2023-07-06T05:53:20ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-03-0111510.1161/JAHA.121.024008S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and PreeclampsiaShathiyah Kulandavelu0Raul A. Dulce1Christopher I. Murray2Michael A. Bellio3Julia Fritsch4Rosemeire Kanashiro‐Takeuchi5Himanshu Arora6Ellena Paulino7Daniel Soetkamp8Wayne Balkan9Jenny E. Van Eyk10Joshua M. Hare11Interdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLMedicine and Heart InstituteCedars Sinai Medical Center Los Angeles CAInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLMedicine and Heart InstituteCedars Sinai Medical Center Los Angeles CAInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLMedicine and Heart InstituteCedars Sinai Medical Center Los Angeles CAInterdisciplinary Stem Cell InstituteUniversity of Miami Miller School of Medicine Miami FLBackground Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S‐nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. Methods and Results Here, we show that mice lacking S‐nitrosoglutathione reductase (GSNOR−⁄−), a denitrosylase regulating protein S‐nitrosylation, exhibit a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation. Reactive oxygen species, NO, and peroxynitrite levels are elevated. Importantly, mass spectrometry reveals elevated placental S‐nitrosylated amino acid residues in GSNOR−⁄− mice. Ascorbate reverses the phenotype except for fetal weight, reduces the difference in the S‐nitrosoproteome, and identifies a unique set of S‐nitrosylated proteins in GSNOR−⁄− mice. Importantly, human preeclamptic placentas exhibit decreased GSNOR activity and increased nitrosative stress. Conclusions Therefore, deficiency of GSNOR creates dysregulation of placental S‐nitrosylation and preeclampsia in mice, which can be rescued by ascorbate. Coupled with similar findings in human placentas, these findings offer valuable insights and therapeutic implications for preeclampsia.https://www.ahajournals.org/doi/10.1161/JAHA.121.024008mouse modelNOpreeclampsiapregnancyS‐nitrosylation |
| spellingShingle | Shathiyah Kulandavelu Raul A. Dulce Christopher I. Murray Michael A. Bellio Julia Fritsch Rosemeire Kanashiro‐Takeuchi Himanshu Arora Ellena Paulino Daniel Soetkamp Wayne Balkan Jenny E. Van Eyk Joshua M. Hare S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease mouse model NO preeclampsia pregnancy S‐nitrosylation |
| title | S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia |
| title_full | S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia |
| title_fullStr | S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia |
| title_full_unstemmed | S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia |
| title_short | S‐Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S‐Nitrosylation and Preeclampsia |
| title_sort | s nitrosoglutathione reductase deficiency causes aberrant placental s nitrosylation and preeclampsia |
| topic | mouse model NO preeclampsia pregnancy S‐nitrosylation |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.024008 |
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