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Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle.
| Content Provider | Scilit |
|---|---|
| Author | Mukohda, Masashi Lu, Ko-Ting Guo, Deng-Fu Wu, Jing Keen, Henry L. Liu, Xuebo Ketsawatsomkron, Pimonrat Stump, Madeliene Rahmouni, Kamal Quelle, Frederick W. Sigmund, Curt D. |
| Copyright Year | 2017 |
| Description | Journal: Hypertension Selective expression of dominant negative (DN) peroxisome proliferator–activated receptor γ (PPARγ) in vascular smooth muscle cells (SMC) results in hypertension, atherosclerosis, and increased nuclear factor-κB (NF-κB) target gene expression. Mesenteric SMC were cultured from mice designed to conditionally express wild-type (WT) or DN-PPARγ in response to Cre recombinase to determine how SMC PPARγ regulates expression of NF-κB target inflammatory genes. SMC-specific overexpression of WT-PPARγ or agonist-induced activation of endogenous PPARγ blunted tumor necrosis factor α (TNF-α)–induced NF-κB target gene expression and activity of an NF-κB–responsive promoter. TNF-α–induced gene expression responses were enhanced by DN-PPARγ in SMC. Although expression of NF-κB p65 was unchanged, nuclear export of p65 was accelerated by WT-PPARγ and prevented by DN-PPARγ in SMC. Leptomycin B, a nuclear export inhibitor, blocked p65 nuclear export and inhibited the anti-inflammatory action of PPARγ. Consistent with a role in facilitating p65 nuclear export, WT-PPARγ coimmunoprecipitated with p65, and WT-PPARγ was also exported from the nucleus after TNF-α treatment. Conversely, DN-PPARγ does not bind to p65 and was retained in the nucleus after TNF-α treatment. Transgenic mice expressing WT-PPARγ or DN-PPARγ specifically in SMC (S-WT or S-DN) were bred with mice expressing luciferase controlled by an NF-κB–responsive promoter to assess effects on NF-κB activity in whole tissue. TNF-α–induced NF-κB activity was decreased in aorta and carotid artery from S-WT but was increased in vessels from S-DN mice. We conclude that SMC PPARγ blunts expression of proinflammatory genes by inhibition of NF-κB activity through a mechanism promoting nuclear export of p65, which is abolished by DN mutation in PPARγ. |
| Related Links | http://hyper.ahajournals.org/content/70/1/174.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472224/pdf http://hyper.ahajournals.org/content/hypertensionaha/early/2017/05/15/HYPERTENSIONAHA.117.09276.full.pdf |
| Ending Page | 182 |
| Page Count | 9 |
| Starting Page | 174 |
| ISSN | 0194911X |
| e-ISSN | 15244563 |
| DOI | 10.1161/HYPERTENSIONAHA.117.09276 |
| Journal | Hypertension |
| Issue Number | 1 |
| Volume Number | 70 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2017-07-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Hypertension Peripheral Vascular Disease |
| Content Type | Text |
| Resource Type | Article |
| Subject | Internal Medicine |
