Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle

Masashi Mukohda; Ko-Ting Lu; Deng-Fu Guo; Jing Wu; Henry L Keen; Xuebo Liu; Pimonrat Ketsawatsomkron; Madeliene Stump; Kamal Rahmouni; Frederick W Quelle; Curt D Sigmund

doi:10.1161/HYPERTENSIONAHA.117.09276

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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

Journal article

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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

Masashi Mukohda, Ko-Ting Lu, Deng-Fu Guo, Jing Wu, Henry L Keen, Xuebo Liu, Pimonrat Ketsawatsomkron, Madeliene Stump, Kamal Rahmouni, Frederick W Quelle, …

Hypertension (Dallas, Tex. 1979), Vol.70(1), pp.174-182

07/2017

DOI: 10.1161/HYPERTENSIONAHA.117.09276

PMCID: PMC5472224

PMID: 28507170

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Abstract

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.

Tumor Necrosis Factor-alpha - metabolism

NF-kappa B - antagonists & inhibitors

Muscle, Smooth, Vascular - metabolism

Anti-Inflammatory Agents - pharmacology

Cells, Cultured

Fatty Acids, Unsaturated - pharmacology

NF-kappa B - metabolism

Muscle, Smooth, Vascular - physiopathology

Hypertension - metabolism

Inflammation - metabolism

Animals

Cell Nucleus - metabolism

Transcription Factor RelA - metabolism

Active Transport, Cell Nucleus - drug effects

Inflammation - genetics

Mice

Hypertension - genetics

Mutation

PPAR gamma - genetics

Details

Title: Subtitle: Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle
Creators: Masashi Mukohda - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Ko-Ting Lu - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Deng-Fu Guo - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Jing Wu - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Henry L Keen - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Xuebo Liu - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Pimonrat Ketsawatsomkron - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Madeliene Stump - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Kamal Rahmouni - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Frederick W Quelle - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Curt D Sigmund - From the Department of Pharmacology and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa. curt-sigmund@uiowa.edu
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.70(1), pp.174-182
Publisher: United States
DOI: 10.1161/HYPERTENSIONAHA.117.09276
PMID: 28507170
PMCID: PMC5472224
ISSN: 0194-911X
eISSN: 1524-4563
Grant note: R01 HL125603 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS R01 HL131689 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 07/2017
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984040284802771

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