ADAM12: A genetic modifier of preclinical peripheral arterial disease

Ayotunde O. 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

15 Scopus citations

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

Keywords

  • Angiogenesis
  • Genetics and genes
  • Ischemia
  • Peripheral vascular disease

ASJC Scopus subject areas

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

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  • Cite this

    Dokun, A. O., Chen, L., Okutsu, M., Farber, C. R., Hazarika, S., Schuyler Jones, W., Craig, D., Marchuk, D. A., John Lye, R., Shah, S. H., & Annex, B. H. (2015). ADAM12: A genetic modifier of preclinical peripheral arterial disease. American Journal of Physiology - Heart and Circulatory Physiology, 309(5), H790-H803. https://doi.org/10.1152/ajpheart.00803.2014