IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension
PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP<sub>3</sub>R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP<sub>3</sub>RI, which mediates intracell...
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MDPI AG
2020-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/10/2280 |
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| author | Siladitta Biswas Baktybek Kojonazarov Stefan Hadzic Michael Majer Ganimete Bajraktari Tatyana Novoyatleva Hossein Ardeschir Ghofrani Friedrich Grimminger Werner Seeger Norbert Weissmann Jens Schlossmann Ralph Theo Schermuly |
| author_facet | Siladitta Biswas Baktybek Kojonazarov Stefan Hadzic Michael Majer Ganimete Bajraktari Tatyana Novoyatleva Hossein Ardeschir Ghofrani Friedrich Grimminger Werner Seeger Norbert Weissmann Jens Schlossmann Ralph Theo Schermuly |
| author_sort | Siladitta Biswas |
| collection | DOAJ |
| description | PKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP<sub>3</sub>R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP<sub>3</sub>RI, which mediates intracellular Ca<sup>2+</sup> release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O<sub>2</sub>) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice. |
| first_indexed | 2024-03-10T15:40:04Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T15:40:04Z |
| publishDate | 2020-10-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-08ce0230c8af4e7a95d65707a96a05782023-11-20T16:52:19ZengMDPI AGCells2073-44092020-10-01910228010.3390/cells9102280IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary HypertensionSiladitta Biswas0Baktybek Kojonazarov1Stefan Hadzic2Michael Majer3Ganimete Bajraktari4Tatyana Novoyatleva5Hossein Ardeschir Ghofrani6Friedrich Grimminger7Werner Seeger8Norbert Weissmann9Jens Schlossmann10Ralph Theo Schermuly11Universities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyDepartment of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyDepartment of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyDepartment of Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, 93040 Regensburg, GermanyUniversities of Giessen and Marburg Lung Centre, German Center for Lung Research (DZL), 35392 Giessen, GermanyPKGs are serine/threonine kinases. PKG1 has two isoforms—PKG1α and β. Inositol trisphosphate receptor (IP<sub>3</sub>R)-associated cGMP-kinase substrate 1 (IRAG1) is a substrate for PKG1β. IRAG1 is also known to further interact with IP<sub>3</sub>RI, which mediates intracellular Ca<sup>2+</sup> release. However, the role of IRAG1 in PH is not known. Herein, WT and IRAG1 KO mice were kept under normoxic or hypoxic (10% O<sub>2</sub>) conditions for five weeks. Animals were evaluated for echocardiographic variables and went through right heart catheterization. Animals were further sacrificed to prepare lungs and right ventricular (RV) for immunostaining, western blotting, and pulmonary artery smooth muscle cell (PASMC) isolation. IRAG1 is expressed in PASMCs and downregulated under hypoxic conditions. Genetic deletion of IRAG1 leads to RV hypertrophy, increase in RV systolic pressure, and RV dysfunction in mice. Absence of IRAG1 in lung and RV have direct impacts on PKG1β expression. Attenuated PKG1β expression in IRAG1 KO mice further dysregulates other downstream candidates of PKG1β in RV. IRAG1 KO mice develop PH spontaneously. Our results indicate that PKG1β signaling via IRAG1 is essential for the homeostasis of PASMCs and RV. Disturbing this signaling complex by deleting IRAG1 can lead to RV dysfunction and development of PH in mice.https://www.mdpi.com/2073-4409/9/10/2280IRAG1PKG1βPulmonary HypertensionPASMCRV dysfunction |
| spellingShingle | Siladitta Biswas Baktybek Kojonazarov Stefan Hadzic Michael Majer Ganimete Bajraktari Tatyana Novoyatleva Hossein Ardeschir Ghofrani Friedrich Grimminger Werner Seeger Norbert Weissmann Jens Schlossmann Ralph Theo Schermuly IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension Cells IRAG1 PKG1β Pulmonary Hypertension PASMC RV dysfunction |
| title | IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension |
| title_full | IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension |
| title_fullStr | IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension |
| title_full_unstemmed | IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension |
| title_short | IRAG1 Deficient Mice Develop PKG1β Dependent Pulmonary Hypertension |
| title_sort | irag1 deficient mice develop pkg1β dependent pulmonary hypertension |
| topic | IRAG1 PKG1β Pulmonary Hypertension PASMC RV dysfunction |
| url | https://www.mdpi.com/2073-4409/9/10/2280 |
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