2016_FRBM.pdf

2019-03-06T14:07:20Z (GMT) by Brian Stansfield
<p>Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease.</p> <p>Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin,</p> <p>leads to accelerated p21Ras activity and phosphorylation of multiple downstream kinases, including Erk</p> <p>and Akt. Nf1 heterozygous (Nf1./-) mice develop a robust neointima that mimics human disease.</p> <p>Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells</p> <p>alone are sufficient to reproduce the enhanced neointima observed in Nf1./- mice. Though the molecular</p> <p>mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of</p> <p>reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound</p> <p>mutant and lineage-restricted mice to demonstrate that Nf1./- macrophages produce excessive ROS,</p> <p>which enhance Nf1./- smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific</p> <p>NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1./- mice. Finally,</p> <p>mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator</p> <p>of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that</p> <p>excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing</p> <p>novels therapies and interventions.</p>