Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, 12325 University of Tennessee Health Sciences Center , Memphis, TN 38163, USA.
Exp Biol Med (Maywood). 2018 Jan;243(2):190-197. doi: 10.1177/1535370217743460. Epub 2017 Dec 3.
Peripheral artery disease is a major health care problem with significant morbidity and mortality. Humans with peripheral artery disease exhibit two major and differential clinical manifestations - intermittent claudication and critical limb ischemia. Individuals with intermittent claudication or critical limb ischemia have overlapping risk factors and objective measures of blood flow. Hence, we hypothesized that variation in genetic make-up may be an important determinant in the severity of peripheral artery disease. Previous studies have identified polymorphism in genes, contributing to extent of atherosclerosis but much less is known about polymorphisms associated with genes that can influence peripheral artery disease severity. This review outlines some of the progress made up-to-date to unravel the molecular mechanisms underlining differential peripheral artery disease severity. By exploring the recovery phenotype of different mouse strains following experimental peripheral artery disease, our group identified the limb salvage-associated quantitative trait locus 1 on mouse chromosome 7 as the first genetic modifier of perfusion recovery and tissue necrosis phenotypes. Furthermore, a number of genes within LSq-1, such as ADAM12, IL-21Rα, and BAG3 were identified as genetic modifiers of peripheral artery disease severity that function through preservation of endothelial and skeletal muscle cells during ischemia. Taken together, these studies suggest manipulation of limb salvage-associated quantitative trait locus 1 genes show great promise as therapeutic targets in the management of peripheral artery disease. Impact statement Peripheral artery disease (PAD) is a major health care problem with significant morbidity and mortality. Individuals with similar atherosclerosis burden do display different severity of disease. This review outlines some of the progress made up-to-date in unraveling the molecular mechanisms underlining differential PAD severity with a focus on the role of the Limb Salvage-associated Quantitative trait locus 1 (LSq-1), a key locus in adaptation to ischemia in PAD.
外周动脉疾病是一个主要的医疗保健问题，具有显著的发病率和死亡率。患有外周动脉疾病的人表现出两种主要的、不同的临床表现——间歇性跛行和严重肢体缺血。间歇性跛行或严重肢体缺血的个体具有重叠的风险因素和血流的客观测量。因此，我们假设遗传构成的差异可能是外周动脉疾病严重程度的一个重要决定因素。先前的研究已经确定了导致动脉粥样硬化程度的基因多态性，但与影响外周动脉疾病严重程度的基因多态性相关的知识要少得多。这篇综述概述了迄今为止在揭示导致外周动脉疾病严重程度不同的分子机制方面取得的一些进展。通过探索不同小鼠品系在实验性外周动脉疾病后的恢复表型，我们的研究小组确定了小鼠 7 号染色体上的肢体挽救相关数量性状基因座 1 是灌注恢复和组织坏死表型的第一个遗传修饰因子。此外，LSq-1 内的许多基因，如 ADAM12、IL-21Rα 和 BAG3，被确定为外周动脉疾病严重程度的遗传修饰因子，它们通过在缺血期间维持内皮细胞和骨骼肌细胞的功能而起作用。总之，这些研究表明，对外周动脉疾病严重程度相关的肢体挽救相关数量性状基因座 1 基因的操作显示出作为外周动脉疾病管理的治疗靶点的巨大潜力。
影响描述：外周动脉疾病（PAD）是一个主要的医疗保健问题，具有显著的发病率和死亡率。尽管个体的动脉粥样硬化负担相似，但他们的疾病严重程度却不同。这篇综述概述了迄今为止在揭示导致外周动脉疾病严重程度不同的分子机制方面取得的一些进展，重点介绍了肢体挽救相关数量性状基因座 1（LSq-1）的作用，LSq-1 是 PAD 适应缺血的关键基因座。
