ADAM12

A genetic modifier of preclinical peripheral arterial disease

Ayotunde Dokun, Lingdan Chen, Mitsuharu Okutsu, Charles R. Farber, Surovi Hazarika, W. Schuyler Jones, Damian Craig, Douglas A. Marchuk, R. John Lye, Svati H. Shah, Brian H. Annex

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.

Original languageEnglish (US)
Pages (from-to)H790-H803
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number5
DOIs
StatePublished - Sep 3 2015
Externally publishedYes

Fingerprint

Disintegrins
Peripheral Arterial Disease
Metalloproteases
Genes
Gene Expression
Limb Salvage
Inbred Strains Mice
Chromosomes, Human, Pair 7
Quantitative Trait Loci
Epidermal Growth Factor
Protein-Tyrosine Kinases
Cell Survival
Anatomy
Ischemia
Endothelial Cells
Hemodynamics
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

ADAM12 : A genetic modifier of preclinical peripheral arterial disease. / Dokun, Ayotunde; Chen, Lingdan; Okutsu, Mitsuharu; Farber, Charles R.; Hazarika, Surovi; Schuyler Jones, W.; Craig, Damian; Marchuk, Douglas A.; John Lye, R.; Shah, Svati H.; Annex, Brian H.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 309, No. 5, 03.09.2015, p. H790-H803.

Research output: Contribution to journalArticle

Dokun, A, Chen, L, Okutsu, M, Farber, CR, Hazarika, S, Schuyler Jones, W, Craig, D, Marchuk, DA, John Lye, R, Shah, SH & Annex, BH 2015, 'ADAM12: A genetic modifier of preclinical peripheral arterial disease', American Journal of Physiology - Heart and Circulatory Physiology, vol. 309, no. 5, pp. H790-H803. https://doi.org/10.1152/ajpheart.00803.2014
Dokun, Ayotunde ; Chen, Lingdan ; Okutsu, Mitsuharu ; Farber, Charles R. ; Hazarika, Surovi ; Schuyler Jones, W. ; Craig, Damian ; Marchuk, Douglas A. ; John Lye, R. ; Shah, Svati H. ; Annex, Brian H. / ADAM12 : A genetic modifier of preclinical peripheral arterial disease. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 309, No. 5. pp. H790-H803.
@article{3f186fbb0d524604b92ca9f3551d969a,
title = "ADAM12: A genetic modifier of preclinical peripheral arterial disease",
abstract = "In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.",
author = "Ayotunde Dokun and Lingdan Chen and Mitsuharu Okutsu and Farber, {Charles R.} and Surovi Hazarika and {Schuyler Jones}, W. and Damian Craig and Marchuk, {Douglas A.} and {John Lye}, R. and Shah, {Svati H.} and Annex, {Brian H.}",
year = "2015",
month = "9",
day = "3",
doi = "10.1152/ajpheart.00803.2014",
language = "English (US)",
volume = "309",
pages = "H790--H803",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - ADAM12

T2 - A genetic modifier of preclinical peripheral arterial disease

AU - Dokun, Ayotunde

AU - Chen, Lingdan

AU - Okutsu, Mitsuharu

AU - Farber, Charles R.

AU - Hazarika, Surovi

AU - Schuyler Jones, W.

AU - Craig, Damian

AU - Marchuk, Douglas A.

AU - John Lye, R.

AU - Shah, Svati H.

AU - Annex, Brian H.

PY - 2015/9/3

Y1 - 2015/9/3

N2 - In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.

AB - In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.

UR - http://www.scopus.com/inward/record.url?scp=84940757010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940757010&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00803.2014

DO - 10.1152/ajpheart.00803.2014

M3 - Article

VL - 309

SP - H790-H803

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 5

ER -