Journal article
ADAM12: a genetic modifier of preclinical peripheral arterial disease
American journal of physiology. Heart and circulatory physiology, Vol.309(5), pp.H790-H803
09/01/2015
DOI: 10.1152/ajpheart.00803.2014
PMCID: PMC4591412
PMID: 26163448
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 C57B1/6 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 C57B1/6 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.
Details
- Title: Subtitle
- ADAM12: a genetic modifier of preclinical peripheral arterial disease
- Creators
- Ayotunde O. Dokun - University of VirginiaLingdan Chen - University of VirginiaMitsuharu Okutsu - University of VirginiaCharles R. Farber - University of VirginiaSurovi Hazarika - University of VirginiaW. Schuyler Jones - Duke UniversityDamian Craig - Duke UniversityDouglas A. Marchuk - Duke UniversityR. John Lye - University of VirginiaSvati H. Shah - Duke UniversityBrian H. Annex - University of Virginia
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.309(5), pp.H790-H803
- Publisher
- Amer Physiological Soc
- DOI
- 10.1152/ajpheart.00803.2014
- PMID
- 26163448
- PMCID
- PMC4591412
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Number of pages
- 14
- Grant note
- R01HL116455; R01HL121635 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) GF12160 / Harold Amos Medical Faculty Development Program R01HL116455 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Robert Wood Johnson Foundation; Robert Wood Johnson Foundation (RWJF)
- Language
- English
- Date published
- 09/01/2015
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297498402771
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