Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo.
Circulation
; 129(11): 1213-24, 2014 Mar 18.
Article
in En
| MEDLINE
| ID: mdl-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 ANDRESULTS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Myeloid Cells
/
Neurofibromin 1
/
Aneurysm
Limits:
Animals
Language:
En
Journal:
Circulation
Year:
2014
Type:
Article