Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo

Fang Li, Brandon D. Downing, Lucy C. Smiley, Julie A. Mund, Matthew R. DiStasi, Waylan K. Bessler, Kara N. Sarchet, Daniel M. Hinds, Lisa M. Kamendulis, Cynthia M. Hingtgen, Jamie Case, D. Wade Clapp, Simon J. Conway, Brian Kevin Stansfield, David A. Ingram

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1213-1224
Number of pages12
JournalCirculation
Volume129
Issue number11
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Neurofibromin 1
Myeloid Cells
Aneurysm
Neurofibromatosis 1
Inborn Genetic Diseases
Simvastatin
Sudden Death
Tumor Suppressor Genes
Angiotensin II
Cell Wall
Transgenic Mice
Blood Vessels
Oral Administration
Oxidative Stress
Homeostasis
Cardiovascular Diseases
Antioxidants
Alleles
Pharmacology
Inflammation

Keywords

  • Aneurysm
  • Antioxidants
  • Genetics
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Inflammation
  • Leukocytes
  • Mice
  • Transgenic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Li, F., Downing, B. D., Smiley, L. C., Mund, J. A., DiStasi, M. R., Bessler, W. K., ... Ingram, D. A. (2014). Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation, 129(11), 1213-1224. https://doi.org/10.1161/CIRCULATIONAHA.113.006320

Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. / Li, Fang; Downing, Brandon D.; Smiley, Lucy C.; Mund, Julie A.; DiStasi, Matthew R.; Bessler, Waylan K.; Sarchet, Kara N.; Hinds, Daniel M.; Kamendulis, Lisa M.; Hingtgen, Cynthia M.; Case, Jamie; Clapp, D. Wade; Conway, Simon J.; Stansfield, Brian Kevin; Ingram, David A.

In: Circulation, Vol. 129, No. 11, 01.01.2014, p. 1213-1224.

Research output: Contribution to journalArticle

Li, F, Downing, BD, Smiley, LC, Mund, JA, DiStasi, MR, Bessler, WK, Sarchet, KN, Hinds, DM, Kamendulis, LM, Hingtgen, CM, Case, J, Clapp, DW, Conway, SJ, Stansfield, BK & Ingram, DA 2014, 'Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo', Circulation, vol. 129, no. 11, pp. 1213-1224. https://doi.org/10.1161/CIRCULATIONAHA.113.006320
Li F, Downing BD, Smiley LC, Mund JA, DiStasi MR, Bessler WK et al. Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation. 2014 Jan 1;129(11):1213-1224. https://doi.org/10.1161/CIRCULATIONAHA.113.006320
Li, Fang ; Downing, Brandon D. ; Smiley, Lucy C. ; Mund, Julie A. ; DiStasi, Matthew R. ; Bessler, Waylan K. ; Sarchet, Kara N. ; Hinds, Daniel M. ; Kamendulis, Lisa M. ; Hingtgen, Cynthia M. ; Case, Jamie ; Clapp, D. Wade ; Conway, Simon J. ; Stansfield, Brian Kevin ; Ingram, David A. / Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. In: Circulation. 2014 ; Vol. 129, No. 11. pp. 1213-1224.
@article{36d1c8e207254c1988b9c00c98c6326c,
title = "Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo",
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.",
keywords = "Aneurysm, Antioxidants, Genetics, Hydroxymethylglutaryl-CoA reductase inhibitors, Inflammation, Leukocytes, Mice, Transgenic",
author = "Fang Li and Downing, {Brandon D.} and Smiley, {Lucy C.} and Mund, {Julie A.} and DiStasi, {Matthew R.} and Bessler, {Waylan K.} and Sarchet, {Kara N.} and Hinds, {Daniel M.} and Kamendulis, {Lisa M.} and Hingtgen, {Cynthia M.} and Jamie Case and Clapp, {D. Wade} and Conway, {Simon J.} and Stansfield, {Brian Kevin} and Ingram, {David A.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1161/CIRCULATIONAHA.113.006320",
language = "English (US)",
volume = "129",
pages = "1213--1224",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

TY - JOUR

T1 - Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo

AU - Li, Fang

AU - Downing, Brandon D.

AU - Smiley, Lucy C.

AU - Mund, Julie A.

AU - DiStasi, Matthew R.

AU - Bessler, Waylan K.

AU - Sarchet, Kara N.

AU - Hinds, Daniel M.

AU - Kamendulis, Lisa M.

AU - Hingtgen, Cynthia M.

AU - Case, Jamie

AU - Clapp, D. Wade

AU - Conway, Simon J.

AU - Stansfield, Brian Kevin

AU - Ingram, David A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Aneurysm

KW - Antioxidants

KW - Genetics

KW - Hydroxymethylglutaryl-CoA reductase inhibitors

KW - Inflammation

KW - Leukocytes

KW - Mice

KW - Transgenic

UR - http://www.scopus.com/inward/record.url?scp=84897555473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897555473&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.113.006320

DO - 10.1161/CIRCULATIONAHA.113.006320

M3 - Article

VL - 129

SP - 1213

EP - 1224

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 11

ER -