A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.
A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1α pathway.
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DOI：
10.1096/fj.202002674rr
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
Monks TJ
中科院分区：
文献类型：
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作者：
Nguyen H;Koh JY;Li H;Islas-Robles A;Meda Venkata SP;Wang JM;Monks TJ
外周动脉疾病（PAD）是糖尿病的主要并发症之一，由于血管生成受损。由于目前没有药物具有令人满意的功效来增强血管形成，因此发现改善血管生成的疗法至关重要。二甲双胍-甲基乙二醛清除反应的咪唑啉酮代谢物（E）-1，1-二甲基-2-（5-甲基-4-氧代-4，5-二氢-1H-咪唑-2-基）胍（IMZ）最近在2型糖尿病患者的尿液中进行了表征和鉴定。在这里，我们报告了IMZ在人脐静脉内皮细胞中的促血管生成作用（增加主动脉发芽、细胞迁移、网络形成和上调多种促血管生成因子）。使用遗传学和药理学方法，我们发现IMZ通过激活内皮型一氧化氮合酶（eNOS）/缺氧诱导因子-1 α（HIF-1α）途径增强血管生成。此外，IMZ显着促进毛细血管密度在体内基质胶塞血管生成模型。最后，在后肢缺血的慢性高血糖小鼠模型中检查了IMZ在缺血后血管生成中的作用。与对照组小鼠相比，我们观察到接受IMZ的小鼠血液灌注改善，毛细血管密度增加，组织坏死减少。我们的数据证明了IMZ的促血管生成作用及其潜在机制，并为开发用于治疗PAD的潜在促血管生成药物提供了结构基础。
Peripheral arterial disease (PAD) is one of the major complications of diabetes due to an impairment in angiogenesis. Since there is currently no drug with satisfactory efficacy to enhance blood vessel formation, discovering therapies to improve angiogenesis is critical. An imidazolinone metabolite of the metformin‐methylglyoxal scavenging reaction, (E)‐1,1‐dimethyl‐2‐(5‐methyl‐4‐oxo‐4,5‐dihydro‐1H‐imidazol‐2‐yl) guanidine (IMZ), was recently characterized and identified in the urine of type‐2 diabetic patients. Here, we report the pro‐angiogenesis effect of IMZ (increased aortic sprouting, cell migration, network formation, and upregulated multiple pro‐angiogenic factors) in human umbilical vein endothelial cells. Using genetic and pharmacological approaches, we showed that IMZ augmented angiogenesis by activating the endothelial nitric oxide synthase (eNOS)/hypoxia‐inducible factor‐1 alpha (HIF‐1α) pathway. Furthermore, IMZ significantly promoted capillary density in the in vivo Matrigel plug angiogenesis model. Finally, the role of IMZ in post‐ischemic angiogenesis was examined in a chronic hyperglycemia mouse model subjected to hind limb ischemia. We observed improved blood perfusion, increased capillary density, and reduced tissue necrosis in mice receiving IMZ compared to control mice. Our data demonstrate the pro‐angiogenic effects of IMZ, its underlying mechanism, and provides a structural basis for the development of potential pro‐angiogenic agents for the treatment of PAD.