Dataset Information

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.

ABSTRACT: Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1+/- mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.

SUBMITTER: Lasater EA

PROVIDER: S-EPMC2827964 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.

Lasater Elisabeth A EA Li Fang F Bessler Waylan K WK Estes Myka L ML Vemula Sasidhar S Hingtgen Cynthia M CM Dinauer Mary C MC Kapur Reuben R Conway Simon J SJ Ingram David A DA

The Journal of clinical investigation 20100215 3

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of ...[more]

PMID: 20160346

Similar Datasets

Project description:Background/objectivesElevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects.Subjects/methodsHemopexin (HPX) was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both the reproductive fat pads and livers of mice representing three strains, LG/J (n=25), SM/J (n=27) and C57Bl/6J (n=19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n=18) and of metabolically normal (n=24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n=18).ResultsHPX expression in mouse adipose tissue, but not in liver, was regulated by dietary fat regardless of genetic background. HPX increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of HPX based on metabolic disease status (P<0.05), and circulating HPX levels were correlated with serum triglycerides in these subjects (r=0.33; P=0.03). HPX was also found in an unbiased proteomic screen of human atherosclerotic plaques and shown to display differential abundance based on the extent of disease and triglyceride content (P<0.05).ConclusionsOur findings suggest that HPX is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

Project description:RationaleActivated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.ObjectiveTo examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.Methods and resultsMiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects.ConclusionsSystemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.

Dataset Information

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.

Publications

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets