Heterozygous inactivation of the NF1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway

Brian K. Stansfield, Waylan K. Bessler, Raghuveer Mali, Julie A. Mund, Brandon Downing, Fang Li, Kara N. Sarchet, Matthew R. DiStasi, Simon Conway, Reuben Kapur, David Ingram

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf1 (Nf11/2) in bone marrow cells enhances neointima formation following arterial injury. Macrophages infiltrate Nf11/2 neointimas, and NF1 patients have increased circulating inflammatory monocytes in their peripheral blood. Therefore, we tested the hypothesis that heterozygous inactivation of Nf1 in myeloid cells is sufficient for neointima formation. Specific ablation of a single copy of the Nf1 gene in myeloid cells alone mobilizes a discrete pro-inflammatory murine monocyte population via a cell autonomous and gene-dosage dependent mechanism. Furthermore, lineage-restricted heterozygous inactivation of Nf1 in myeloid cells is sufficient to reproduce the enhanced neointima formation observed in Nf11/2 mice when compared with wild-type controls, and homozygous inactivation of Nf1 in myeloid cells amplified the degree of arterial stenosis after arterial injury. Treatment of Nf11/2 mice with rosuvastatin, a stain with anti-inflammatory properties, significantly reduced neointima formation when compared with control. These studies identify neurofibromin-deficient myeloid cells as critical cellular effectors of Nf11/2 neointima formation and propose a potential therapeutic for NF1 cardiovascular disease.

Original languageEnglish
Article numberdds502
Pages (from-to)977-988
Number of pages12
JournalHuman Molecular Genetics
Volume22
Issue number5
DOIs
StatePublished - Mar 2013

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Neurofibromatosis 1 Genes
Neointima
Neurofibromatosis 1
Myeloid Cells
Neurofibromin 1
Monocytes
Cardiovascular Diseases
Gene Dosage
Wounds and Injuries
Sudden Death
Tumor Suppressor Genes
Bone Marrow Cells
Rosuvastatin Calcium
Pathologic Constriction
Anti-Inflammatory Agents
Coloring Agents
Ischemia
Macrophages
Morbidity
Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Heterozygous inactivation of the NF1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway. / Stansfield, Brian K.; Bessler, Waylan K.; Mali, Raghuveer; Mund, Julie A.; Downing, Brandon; Li, Fang; Sarchet, Kara N.; DiStasi, Matthew R.; Conway, Simon; Kapur, Reuben; Ingram, David.

In: Human Molecular Genetics, Vol. 22, No. 5, dds502, 03.2013, p. 977-988.

Research output: Contribution to journalArticle

Stansfield, Brian K. ; Bessler, Waylan K. ; Mali, Raghuveer ; Mund, Julie A. ; Downing, Brandon ; Li, Fang ; Sarchet, Kara N. ; DiStasi, Matthew R. ; Conway, Simon ; Kapur, Reuben ; Ingram, David. / Heterozygous inactivation of the NF1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 5. pp. 977-988.
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