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Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor ? Impairs Nuclear Export of Nuclear Factor-?B p65 in Vascular Smooth Muscle.

ABSTRACT: Selective expression of dominant negative (DN) peroxisome proliferator-activated receptor ? (PPAR?) in vascular smooth muscle cells (SMC) results in hypertension, atherosclerosis, and increased nuclear factor-?B (NF-?B) target gene expression. Mesenteric SMC were cultured from mice designed to conditionally express wild-type (WT) or DN-PPAR? in response to Cre recombinase to determine how SMC PPAR? regulates expression of NF-?B target inflammatory genes. SMC-specific overexpression of WT-PPAR? or agonist-induced activation of endogenous PPAR? blunted tumor necrosis factor ? (TNF-?)-induced NF-?B target gene expression and activity of an NF-?B-responsive promoter. TNF-?-induced gene expression responses were enhanced by DN-PPAR? in SMC. Although expression of NF-?B p65 was unchanged, nuclear export of p65 was accelerated by WT-PPAR? and prevented by DN-PPAR? in SMC. Leptomycin B, a nuclear export inhibitor, blocked p65 nuclear export and inhibited the anti-inflammatory action of PPAR?. Consistent with a role in facilitating p65 nuclear export, WT-PPAR? coimmunoprecipitated with p65, and WT-PPAR? was also exported from the nucleus after TNF-? treatment. Conversely, DN-PPAR? does not bind to p65 and was retained in the nucleus after TNF-? treatment. Transgenic mice expressing WT-PPAR? or DN-PPAR? specifically in SMC (S-WT or S-DN) were bred with mice expressing luciferase controlled by an NF-?B-responsive promoter to assess effects on NF-?B activity in whole tissue. TNF-?-induced NF-?B activity was decreased in aorta and carotid artery from S-WT but was increased in vessels from S-DN mice. We conclude that SMC PPAR? blunts expression of proinflammatory genes by inhibition of NF-?B activity through a mechanism promoting nuclear export of p65, which is abolished by DN mutation in PPAR?.

SUBMITTER: Mukohda M

PROVIDER: S-EPMC5472224 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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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.

Mukohda Masashi M Lu Ko-Ting KT Guo Deng-Fu DF Wu Jing J Keen Henry L HL Liu Xuebo X Ketsawatsomkron Pimonrat P Stump Madeliene M Rahmouni Kamal K Quelle Frederick W FW Sigmund Curt D CD

Hypertension (Dallas, Tex. : 1979) 20170515 1

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 o ...[more]

PMID: 28507170

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor ? Impairs Nuclear Export of Nuclear Factor-?B p65 in Vascular Smooth Muscle.

Publications

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

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