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

Hypertension
Masashi MukohdaCurt D Sigmund

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 aft...Continue Reading

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Citations

Jun 7, 2018·Physiological Reviews·Steven J ForresterSatoru Eguchi
Mar 22, 2019·The Journal of Clinical Investigation·Masashi MukohdaCurt D Sigmund
Dec 4, 2019·Current Opinion in Nephrology and Hypertension·Shi Fang, Curt D Sigmund
Nov 13, 2019·Scientific Reports·Roberto Palacios-RamírezMaría J Alonso
Aug 14, 2019·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Masashi Mukohda
Mar 5, 2021·Journal of Smooth Muscle Research = Nihon Heikatsukin Gakkai Kikanshi·Masashi Mukohda, Hiroshi Ozaki
Feb 17, 2021·British Journal of Pharmacology·Yumei QueXiaoyong Tong
Oct 19, 2017·Biochemical and Biophysical Research Communications·Junjiang ChenHongjun Sang
Apr 2, 2021·Circulation Research·Shi FangCurt D Sigmund

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