HIPK2下调对心肌缺血再灌注损伤的保护作用及机制研究

In patients with myocardial infarction (MI), timely and effective myocardial reperfusion can reduce MI injury and limit MI size. However, reperfusion itself can induce cardiomyocytes death, known as myocardial ischemia/reperfusion(I/R) injury. It still lacks therapy for I/R injury, and the identification of novel therapeutic targets is highly needed. In our previous research, we found that the expression of homeodomain-interacting protein kinase 2 (HIPK2) was elevated in MI region. Furthermore, HIPK2 knockout could protect against I/R injury in mice. These data indicate that HIPK2 might be a potential therapeutic target for I/R injury. In the present project, we will firstly identify the role of HIPK2 in I/R injury based on both loss-of-function and gain-of-function experiments. I/R injury model will be used in vivo with HIPK2 knockout mice and HIPK2 transgenic mice. Oxygen glucose deprivation/recovery (OGD/R) induced cardiomyocytes apoptosis model will be used in vitro with HIPK2-overexpressing lentivirus and HIPK2-interference lentivirus infection. In mechanism, based on our data, we propose mouse double minute 2 homolog (MDM2) to be a downstream gene of HIPK2. Next, we will perform the rescue experiments in vitro and in vivo to elucidate the regulation of HIPK2 to MDM2 in I/R injury. Our project will prove the protective effect of HIPK2 inhibition upon I/R injury and provide a novel therapeutic target for I/R injury.

再灌注治疗是有效缓解心肌缺血的方法，但是再灌注本身也会引起心肌细胞的死亡。心肌缺血再灌注损伤目前缺乏治愈方法，寻找新的治疗靶点具有重要意义。我们的前期研究发现，HIPK2在小鼠心肌梗死组织中表达上调；HIPK2敲除可以保护小鼠心肌缺血再灌注损伤。本项目将在动物水平（心肌特异性敲除小鼠和过表达小鼠）和细胞水平（氧葡萄糖剥夺/恢复诱导凋亡）明确HIPK2在心肌缺血再灌注损伤中的功能。在机制方面，我们的数据表明MDM2可能是HIPK2的下游分子。我们将明确HIPK2下游调控机制；阐释HIPK2如何调控MDM2。本项目将明确HIPK2在防治心肌缺血再灌注损伤中的作用及分子机制，为心肌缺血再灌注损伤的治疗提供新靶点。

心肌梗死严重危害患者健康与生存，发现心肌梗死的新靶点有助于疾病的治疗与防治。前期工作中，我们发现HIPK2蛋白在小鼠心肌梗死组织中表达上调，而且HIPK2敲除可以明细改善小鼠的心肌梗塞。这些结果提示我们HIPK2可能参与心肌梗死的生物学过程。执行项目计划的过程中，我们发现在体外和体内的心肌梗死相关模型中，HIPK2的抑制都可以冥想改善心肌细胞的凋亡，而且进一步的分子机制结果表明，HIPK2可以与P53蛋白直接结合，且影响其磷酸化激活。项目的执行，进一步确认了HIPK2在心肌梗死过程中的功能并解析了其发挥功能的分子机制，提示其有可能成为心肌梗死的防治新靶点。