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  • Title: Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor γ Impairs Nuclear Export of Nuclear Factor-κB p65 in Vascular Smooth Muscle.
    Author: Mukohda M, Lu KT, Guo DF, Wu J, Keen HL, Liu X, Ketsawatsomkron P, Stump M, Rahmouni K, Quelle FW, Sigmund CD.
    Journal: Hypertension; 2017 Jul; 70(1):174-182. PubMed ID: 28507170.
    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.
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