Journal article
Neurofibromin-Deficient Myeloid Cells Are Critical Mediators of Aneurysm Formation In Vivo
Circulation (New York, N.Y.), Vol.129(11), pp.1213-1224
03/18/2014
DOI: 10.1161/CIRCULATIONAHA.113.006320
PMCID: PMC3960343
PMID: 24370551
Abstract
Background Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in the development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown.
Method and Results With the use of an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1(+/-) aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin reduced aneurysm formation in Nf1(+/-) mice.
Conclusion These data provide genetic and pharmacological evidence that Nf1(+/-) myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.
Details
- Title: Subtitle
- Neurofibromin-Deficient Myeloid Cells Are Critical Mediators of Aneurysm Formation In Vivo
- Creators
- Fang Li - Indiana University School of MedicineBrandon D. Downing - Indiana University School of MedicineLucy C. Smiley - Indiana University School of MedicineJulie A. Mund - Indiana University School of MedicineMatthew R. DiStasi - Indiana University School of MedicineWaylan K. Bessler - Indiana University School of MedicineKara N. Sarchet - Indiana University School of MedicineDaniel M. Hinds - Indiana University School of MedicineLisa M. Kamendulis - Indiana University School of MedicineCynthia M. Hingtgen - Indiana University School of MedicineJamie Case - Indiana University School of MedicineD. Wade Clapp - Indiana University School of MedicineSimon J. Conway - Indiana University School of MedicineBrian K. Stansfield - Indiana University School of MedicineDavid A. Ingram - Indiana University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.129(11), pp.1213-1224
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/CIRCULATIONAHA.113.006320
- PMID
- 24370551
- PMCID
- PMC3960343
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Number of pages
- 12
- Grant note
- P50NS052606 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) TL1RR025759 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) K12HD000850 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) K12 HD000850 / Eunice Kennedy Shriver National Institute of Child Health & Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) UL1TR001108 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 03/18/2014
- Academic Unit
- Pulmonary Medicine; Stead Family Department of Pediatrics
- Record Identifier
- 9984354009202771
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