ADAM12: a genetic modifier of preclinical peripheral arterial disease
ADAM12: a genetic modifier of preclinical peripheral arterial disease
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DOI：
10.1152/ajpheart.00803.2014
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发表时间：
2015-09-01
影响因子：
4.8
通讯作者：
Annex, Brian H.
中科院分区：
文献类型：
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作者：
Dokun, Ayotunde O.;Chen, Lingdan;Annex, Brian H.
在先前来自多个组的研究中，实验性外周动脉疾病(PAD)的结果在不同近交系小鼠之间有很大差异。同样，在患有PAD的人中，即使在危险因素、疾病解剖、动脉硬化负担和血流动力学指标方面有相似之处，疾病结果也不同。此前，我们在小鼠7号染色体上发现了一个基因座，即肢体挽救相关数量性状基因座1(LSQ-1)，它足以改变实验性PAD后的结果。我们比较了Balb/c小鼠和C57B1/6小鼠LSq-1基因的表达，发现去整合素和金属蛋白酶基因12(ADAM12)的表达差异最大。体内ADAM12表达的增强改善了Balb/c小鼠实验性PAD后的结果，而敲除ADAM12使C57B1/6小鼠的结果变得更糟。在体外，ADAM12的表达调节缺血时内皮细胞的增殖、存活和血管生成，这似乎依赖于具有Ig样和EGF样结构域2(Tie2)激活的酪氨酸激酶。ADAM12足以改变小鼠PAD的严重程度，这可能是通过调节Tie2而发生的。
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.