Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease.
Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease.
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DOI：
10.1177/1358863x19866254
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发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Dokun AO
中科院分区：
文献类型：
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作者：
Alleboina S;Ayalew D;Peravali R;Chen L;Wong T;Dokun AO
外周动脉疾病（PAD）是由心脏外血管（尤其是下肢血管）的动脉粥样硬化闭塞引起的。血管生成是 PAD 血管闭塞的一种关键生理反应，但我们对血管生成涉及的分子机制的理解并不完整。双特异性磷酸酶 5 (DUSP5) 已被证明在胚胎血管发育中发挥关键作用，但其在缺血后血管生成中的作用尚不清楚。我们诱导小鼠后肢缺血，发现缺血后肢中 DUSP5 表达显着上调。此外，体内敲低 DUSP5 会导致缺血肢体的灌注恢复受损，并与肢体坏死增加相关。体外研究表明，暴露于缺血的人内皮细胞中 DUSP5 上调，而这些缺血内皮细胞中 DUSP5 的敲低会导致内皮细胞增殖和血管生成受损，但不会改变细胞凋亡。最后，我们表明 DUSP5 对缺血后血管生成的这些影响是 DUSP5 依赖性 ERK1/2 磷酸化和 p21 蛋白表达减少的结果。因此，我们已经确定了 DUSP5 在缺血后血管生成中的作用，并暗示 DUSP5-ERK-p21 途径可以作为调节 PAD 缺血后血管生成的治疗靶点。
Peripheral artery disease (PAD) is caused by atherosclerotic occlusions of vessels outside the heart, particularly those of the lower extremities. Angiogenesis is one critical physiological response to vessel occlusion in PAD, but our understanding of the molecular mechanisms involved in angiogenesis is incomplete. Dual specificity phosphatase 5 (DUSP5) has been shown to play a key role in embryonic vascular development, but its role in post-ischemic angiogenesis is not known. We induced hind limb ischemia in mice and found robust upregulation of DUSP5 expression in ischemic hind limbs. Moreover, in vivo knockdown of DUSP5 resulted in impaired perfusion recovery in ischemic limbs and was associated with increased limb necrosis. In vitro studies showed upregulation of DUSP5 in human endothelial cells exposed to ischemia, and knockdown of DUSP5 in these ischemic endothelial cells resulted in impaired endothelial cell proliferation and angiogenesis, but did not alter apoptosis. Finally, we show that these effects of DUSP5 on post-ischemic angiogenesis are a result of DUSP5-dependent decrease in ERK1/2 phosphorylation and p21 protein expression. Thus, we have identified a role of DUSP5 in post-ischemic angiogenesis and implicated a DUSP5-ERK-p21 pathway that may serve as a therapeutic target for the modulation of post-ischemic angiogenesis in PAD.