IKKβ links vascular inflammation to obesity and atherosclerosis

Sui, Yipeng; Park, Sehyung; Xu, Jinxian; Monette, Sébastien; Helsley, Robert N; Han, Seong‐Su; Zhou, Changcheng

doi:10.1084/jem.20131281

Cited by 58 publications

(94 citation statements)

References 75 publications

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“…These results are in good agreement with a study by Toure et al (42), who observed reduced neointimal formation in global mDia1 knockout mice. Since SM22α expression has been detected in some myeloid cells (43, 44) and macrophage infiltration has been shown to promote neointima formation, it is difficult to completely eliminate a role for these cells in our model. However, since the majority of neointima cells in our injury model are SMC, we believe that mDia signaling plays a SMC autonomous role in neointimal formation most likely by promoting SMC migration from the medial layer.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype

Weise-Cross

Taylor

Mack

2015

ATVB

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Objective We and others have previously shown that RhoA-dependent stimulation of myocardin related transcription factor (MRTF) nuclear localization promotes smooth muscle cell (SMC) marker gene expression. The goal of the present study was to provide direct in vivo evidence that actin polymerization by the diaphanous-related formins contributes to the regulation of SMC differentiation and/or phenotype. Approach and Results Conditional cre-based genetic approaches were used to over-express a well-characterized dominant negative variant of mDia1 (DNmDia) in SMC. DNmDia expression in SM22 expressing cells resulted in embryonic and perinatal lethality in ~20% of mice due to defects in myocardial development and SMC investment of peripheral vessels. While most DNmDia+/SM22Cre+ mice exhibited no overt phenotype, the re-expression of SMC differentiation marker gene expression that occurs following carotid artery ligation was delayed, and this effect was accompanied by a significant decrease in MRTF-A nuclear localization. Interestingly, neointima growth was inhibited by expression of DNmDia in SMC and this was likely due to a defect in directional SMC migration and not to defects in SMC proliferation or survival. Finally, by using the tamoxifen-inducible SM MHCCreERT2 line, we showed that SMC-specific induction of DNmDia in adult mice decreased SMC marker gene expression. Conclusions Our demonstration that diaphanous-related formin signaling plays a role in heart and vascular development and the maintenance of SMC phenotype provides important new evidence that Rho/actin/MRTF signaling plays a critical role in cardiovascular function.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype

Weise-Cross

Taylor

Mack

2015

ATVB

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“…EMSA was performed as described previously (38,42). Briefly, NPC1L1/DR-4 and CYP3A4/ER-6 probes were created by annealing the oligonucleotides 5Ј-GGGCAGATCACTT-…”

Section: Electrophoretic Mobility Shift Assay (Emsa)mentioning

confidence: 99%

“…Western blot analysis was performed as previously described (42). Proteins were isolated from cells or mouse tissues by homogenization in RIPA buffer with complete mini protease inhibitor cocktail (Roche).…”

Section: Western Blot Analysismentioning

confidence: 99%

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Sui

Helsley

Park

et al. 2015

Molecular Endocrinology

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Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activation of the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Here we report an important role of intestinal PXR in linking xenobiotic exposure and hyperlipidemia. We identified tributyl citrate (TBC), one of a large group of Food and Drug Administration-approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Interestingly, TBC activated intestinal PXR but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. TBC-mediated PXR activation stimulated the expression of an essential cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), in the intestine. Promoter analysis revealed a DR-4 type of PXR response element in the human NPC1L1 promoter, and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased lipid uptake by human and murine intestinal cells and deficiency of PXR inhibited TBC-elicited lipid uptake. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating the adverse effects of EDCs on cardiovascular disease risk in humans.

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“…The systemic inflammation that is associated with atherosclerosis is partly derived from adipose tissue [22,23]. In our previous study we found that hematopoietic C/EBPβ deletion in wildtype mice prevented high fat diet-mediated induction of adipose tissue inflammation [11].…”

Section: Resultsmentioning

confidence: 99%

C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis

et al. 2016

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Background and Objective Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBPβ is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBPβ's role in atherosclerotic progression has not been examined. We assessed the impact of hematopoietic CEBPβ deletion in ApoE−/− mice on hyperlipidemia, inflammatory responses and lesion formation in the aorta. Methods and Results ApoE−/− mice were reconstituted with bone marrow cells derived from either WT or C/EBPβ−/− mice and placed on low fat or high fat/high cholesterol diet for 11 weeks. Hematopoietic C/EBPβ deletion in ApoE−/− mice reduced blood and hepatic lipids and gene expression of hepatic stearoyl CoA desaturase 1 and fatty acid synthase while expression of ATP binding cassette transporter G1, cholesterol 7-alpha-hydroxylase, and liver X receptor alpha genes were significantly increased. ApoE−/− mice reconstituted with C/EBPβ−/− bone marrow cells also significantly reduced blood cytokine levels and reduced lesion area in aortic sinuses compared with ApoE−/− mice reconstituted with WT bone marrow cells. Silencing of C/EBPβ in RAW264.7 macrophage cells prevented oxLDL-mediated foam cell formation and inflammatory cytokine secretion in conditioned medium. Conclusion C/EBPβ in hematopoietic cells is crucial to regulate diet-induced inflammation, hyperlipidemia and atherosclerosis development.

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IKKβ links vascular inflammation to obesity and atherosclerosis

Abstract: IKKβ functions in smooth muscle cells to regulate vascular inflammatory responses and atherosclerosis development.

Cited by 58 publications

References 75 publications

Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype

Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis

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