Inhibition of poly-ADP ribose polymerase enzyme activity prevents hyperglycemia-induced impairment of angiogenesis during wound healing.
Inhibition of poly-ADP ribose polymerase enzyme activity prevents hyperglycemia-induced impairment of angiogenesis during wound healing.
复制标题
抑制聚 ADP 核糖聚合酶活性可防止伤口愈合过程中高血糖引起的血管生成受损。
DOI：
10.1111/wrr.12216
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Intine,RobertV
中科院分区：
文献类型：
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作者：
SarrasJr,MichaelP;Mason,Samantha;McAllister,Geoffrey;Intine,RobertV
我们先前报道了一种I型糖尿病（DM）的斑马鱼模型，该模型可用于研究同一条鱼内的高血糖（HG）和代谢记忆（MM）状态。在临床上，MM被定义为即使在血糖控制不佳后糖尿病并发症的持续存在。在我们的斑马鱼模型中，MM发生在β细胞再生之后，这使鱼类恢复正常。在HG期间，鱼获得反映DM患者中观察到的并发症的组织缺陷，并且这些缺陷在鱼恢复正常（MM）后持续存在。诱导糖尿病并发症的统一机制涉及由HG刺激聚ADP核糖聚合酶（Parp）活性引发的级联事件。此外，最近的证据表明，HG诱导的Parp活性刺激与MM状态和并发症的持续性相关的表观遗传机制的变化。在这里，我们报告说，创伤诱导的血管生成受损的DM和仍然受损时，鱼恢复到正常血糖状态。此外，抑制Parp活性可防止观察到的HG诱导的伤口血管生成缺陷。这种方法可以识别分子靶点，这将为治疗发现提供潜在的新途径，因为血管生成失衡与所有HG受损组织相关。
We previously reported a zebrafish model of type I diabetes mellitus (DM) that can be used to study the hyperglycemic (HG) and metabolic memory (MM) states within the same fish. Clinically, MM is defined as the persistence of diabetic complications even after glycemic control is pharmacologically achieved. In our zebrafish model, MM occurs following β‐cell regeneration, which returns fish to euglycemia. During HG, fish acquire tissue deficits reflective of the complications seen in patients with DM and these deficits persist after fish return to euglycemia (MM). The unifying mechanism for the induction of diabetic complications involves a cascade of events that is initiated by the HG stimulation of poly‐ADP ribose polymerase enzyme (Parp) activity. Additionally, recent evidence shows that the HG induction of Parp activity stimulates changes in epigenetic mechanisms that correlate with the MM state and the persistence of complications. Here we report that wound‐induced angiogenesis is impaired in DM and remains impaired when fish return to a euglycemic state. Additionally, inhibition of Parp activity prevented the HG‐induced wound angiogenesis deficiency observed. This approach can identify molecular targets that will provide potential new avenues for therapeutic discovery as angiogenesis imbalances are associated with all HG‐damaged tissues.