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

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