NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension
Aim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2R899X mouse lung an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2014-05-01
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| Series: | Diseases |
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| Online Access: | http://www.mdpi.com/2079-9721/2/2/148 |
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| author | Megha Talati Haitham Mutlak Kirk B. Lane Wei Han Anna Hemnes Outi Mutlak Tom Blackwell Rinat Zaynagetdinov Timothy S. Blackwell James West |
| author_facet | Megha Talati Haitham Mutlak Kirk B. Lane Wei Han Anna Hemnes Outi Mutlak Tom Blackwell Rinat Zaynagetdinov Timothy S. Blackwell James West |
| author_sort | Megha Talati |
| collection | DOAJ |
| description | Aim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling. Conclusion: NF-κB activation exacerbates, but is not required for Bmpr2-related PH. Pulmonary vascular-specific activation of NF-κB may be a “second hit” that drives penetrance in heritable PH. |
| first_indexed | 2024-12-12T21:22:27Z |
| format | Article |
| id | doaj.art-df81727870de4bbc8cebe6c5402aeeca |
| institution | Directory Open Access Journal |
| issn | 2079-9721 |
| language | English |
| last_indexed | 2024-12-12T21:22:27Z |
| publishDate | 2014-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Diseases |
| spelling | doaj.art-df81727870de4bbc8cebe6c5402aeeca2022-12-22T00:11:32ZengMDPI AGDiseases2079-97212014-05-012214816710.3390/diseases2020148diseases2020148NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary HypertensionMegha Talati0Haitham Mutlak1Kirk B. Lane2Wei Han3Anna Hemnes4Outi Mutlak5Tom Blackwell6Rinat Zaynagetdinov7Timothy S. Blackwell8James West9Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Johann Wolfgang Goethe, Frankfurt 60590, GermanyDivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO 80045, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADivision of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USAAim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling. Conclusion: NF-κB activation exacerbates, but is not required for Bmpr2-related PH. Pulmonary vascular-specific activation of NF-κB may be a “second hit” that drives penetrance in heritable PH.http://www.mdpi.com/2079-9721/2/2/148pulmonary arterial hypertensionbone morphogenic protein receptor type 2NF-κBinflammation |
| spellingShingle | Megha Talati Haitham Mutlak Kirk B. Lane Wei Han Anna Hemnes Outi Mutlak Tom Blackwell Rinat Zaynagetdinov Timothy S. Blackwell James West NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension Diseases pulmonary arterial hypertension bone morphogenic protein receptor type 2 NF-κB inflammation |
| title | NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension |
| title_full | NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension |
| title_fullStr | NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension |
| title_full_unstemmed | NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension |
| title_short | NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension |
| title_sort | nf κb activation exacerbates but is not required for murine bmpr2 related pulmonary hypertension |
| topic | pulmonary arterial hypertension bone morphogenic protein receptor type 2 NF-κB inflammation |
| url | http://www.mdpi.com/2079-9721/2/2/148 |
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