Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease.
Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease.
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DOI：
10.3390/ijms23010429
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发表时间：
2021-12-31
影响因子：
5.6
通讯作者：
Dokun AO
中科院分区：
文献类型：
--
作者：
Lamin V;Verry J;Eigner-Bybee I;Fuqua JD;Wong T;Lira VA;Dokun AO
1型糖尿病(DM1)和2型糖尿病(DM2)均与外周动脉疾病(PAD)截肢风险增加相关。糖尿病如何导致不良的PAD预后尚不清楚，但在DM1和DM2中可能通过不同的机制发生。在此之前，我们发现去整合素和金属蛋白酶基因12(ADAM12)是脑缺血后再灌流恢复的关键遗传调节因子。在实验垫中，我们发现ADAM12受到miR-29a的调节，这种调节在DM1中的缺血内皮细胞中受到损害，导致血流灌注恢复不良。在这里，我们研究了在DM2的设置下，实验垫中miR-29a对ADAM12的调节是否发生了变化。我们还探讨了调节miR-29a和ADAM12的表达是否可以改善DM2小鼠的血流灌注恢复和肢体功能。我们的结果表明，在DM2小鼠的缺血肢体中，miR-29a的表达下调不明显，ADAM12的上调受到损害。抑制miR-29a和ADAM12的过表达可改善灌注恢复，减少骨骼肌损伤，改善肌肉功能，并增加裂解的Tie 2和AKT的磷酸化。因此，抑制miR-29a和或增强ADAM12可能通过调节Tie 2和AKT信号来改善DM2的实验PAD结果。
Both Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with an increased risk of limb amputation in peripheral arterial disease (PAD). How diabetes contributes to poor PAD outcomes is poorly understood but may occur through different mechanisms in DM1 and DM2. Previously, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. In an experimental PAD, we showed that ADAM12 is regulated by miR-29a and this regulation is impaired in ischemic endothelial cells in DM1, contributing to poor perfusion recovery. Here we investigated whether miR-29a regulation of ADAM12 is altered in experimental PAD in the setting of DM2. We also explored whether modulation of miR-29a and ADAM12 expression can improve perfusion recovery and limb function in mice with DM2. Our result showed that in the ischemic limb of mice with DM2, miR-29a expression is poorly downregulated and ADAM12 upregulation is impaired. Inhibition of miR-29a and overexpression of ADAM12 improved perfusion recovery, reduced skeletal muscle injury, improved muscle function, and increased cleaved Tie 2 and AKT phosphorylation. Thus, inhibition of miR-29a and or augmentation of ADAM12 improves experimental PAD outcomes in DM2 likely through modulation of Tie 2 and AKT signalling.
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