Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans

Waylan K. Bessler, Farlyn Z. Hudson, Hanfang Zhang, Valerie Harris, Yusi Wang, Julie A. Mund, Brandon Downing, David A. Ingram, Jamie Case, David J Fulton, Brian Kevin Stansfield

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease. Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21Ras activity and phosphorylation of multiple downstream kinases, including Erk and Akt. Nf1 heterozygous (Nf1+/-) mice develop a robust neointima that mimics human disease. Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells alone are sufficient to reproduce the enhanced neointima observed in Nf1+/- mice. Though the molecular mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound mutant and lineage-restricted mice to demonstrate that Nf1+/- macrophages produce excessive ROS, which enhance Nf1+/- smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1+/- mice. Finally, mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing novels therapies and interventions.

Original languageEnglish (US)
Pages (from-to)212-222
Number of pages11
JournalFree Radical Biology and Medicine
Volume97
DOIs
StatePublished - Aug 1 2016

Fingerprint

Neurofibromin 1
Neurofibromatosis 1
Macrophages
Reactive Oxygen Species
Neointima
Pathologic Constriction
Phosphorylation
Oxidative stress
NADPH Oxidase
Cell proliferation
Oxidants
Muscle
Tumors
Mutation
Phosphotransferases
Genes
Myeloid Cells
Tumor Suppressor Genes
DNA Damage
Smooth Muscle Myocytes

Keywords

  • Apocynin
  • Macrophage
  • Monocyte
  • NADPHoxidase
  • Neointima
  • Neurofibromatosis
  • Ras
  • Reactiveoxygenspecies
  • Smooth musclecell
  • Superoxide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans. / Bessler, Waylan K.; Hudson, Farlyn Z.; Zhang, Hanfang; Harris, Valerie; Wang, Yusi; Mund, Julie A.; Downing, Brandon; Ingram, David A.; Case, Jamie; Fulton, David J; Stansfield, Brian Kevin.

In: Free Radical Biology and Medicine, Vol. 97, 01.08.2016, p. 212-222.

Research output: Contribution to journalArticle

Bessler, Waylan K. ; Hudson, Farlyn Z. ; Zhang, Hanfang ; Harris, Valerie ; Wang, Yusi ; Mund, Julie A. ; Downing, Brandon ; Ingram, David A. ; Case, Jamie ; Fulton, David J ; Stansfield, Brian Kevin. / Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans. In: Free Radical Biology and Medicine. 2016 ; Vol. 97. pp. 212-222.
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