Impact of the Plexin C1 - Semaphorin 7A axis during myocardial ischemia reperfusion injury

缺血再灌注损伤(IR)是临床医学中影响很大一部分患者的一种有害状态。心肌缺血再灌注是IR损伤的最主要形式，并与显著的死亡率相关。在IR损伤期间，中性粒细胞渗入受影响的区域，加剧组织炎症，从而增加组织损伤。我们最近的工作表明，不仅经典的细胞因子/趋化因子系统引导白细胞迁移，而且神经元引导蛋白系统也引导白细胞迁移。在这个项目的最初资金阶段，我们能够证明引导蛋白Semaphorin 7A(Sema7A)是在组织缺氧时诱导的，并且引导受体Plexin C1(PLXNC1)参与了急性炎症的控制。然而，关于Sema7A PLXNC1轴在心肌IR损伤过程中的重要相互作用，目前还知之甚少。在初步实验中，我们发现Sema7A的基因缺失显著减少了心肌组织的损伤程度，而且这种作用似乎是由PLXNC1介导的。因此，我们建议在该项目的第二个资助期破译Sema7A PLXNC1轴在心肌缺血再灌注损伤中的作用。我们将研究Sema7A PLXNC1相互作用及其组织特异性表达在白细胞募集中的作用。接下来，我们将利用红细胞、内皮细胞和溶菌酶阳性细胞中Sema7A的组织特异性缺失来确定Sema7A在心肌组织损伤中的来源和影响。然后，我们还将使用组织特异性的PLXNC1缺失来描述其对白细胞募集、组织炎症、血小板-中性粒细胞复合体形成以及心肌IR损伤程度的影响。这将为Sema7A PLXNC1受体配体对在与白细胞募集、组织炎症和IR相关的条件下所起的作用提供新的证据。未来对心肌IR损伤和其他几种相关疾病的治疗可能基于这些发现。

Ischemia reperfusion injury (IR) is a detrimental condition that affects a significant portion of patients in clinical medicine. Myocardial ischemia reperfusion is the most prominent form of IR injury and is associated with significant mortality. During IR injury neutrophils infiltrate the affected areas, enhance tissue inflammation and as such increase tissue injury. Recent work by us has shown that not only the classical cytokine/ chemokine system guides leukocyte migration but also the system of neuronal guidance proteins. In the initial funding period of this project we were able to demonstrate that the guidance protein Semaphorin 7A (Sema7A) is induced during tissue hypoxia and that the guidance receptor Plexin C1 (PLXNC1) is involved into the control of acute inflammation. However, not much is known about the important interaction of the Sema7A PLXNC1 axis during myocardial IR injury. In preliminary experiments we found that genetic deletion of Sema7A significantly reduces the extent of myocardial tissue injury and that this effect seems to be mediated by PLXNC1. Therefore we propose here for the second funding period of this project to decipher the role of Sema7A PLXNC1 axis during myocardial IR injury. We will investigate the role of Sema7A PLXNC1 interaction and their tissue specific expression for leukocyte recruitment. Next, we will then use tissue specific deletion of Sema7A in erythrocytes, endothelial cells and lysozyme positive cells to identify the origin and impact of Sema7A for myocardial tissue injury. We will then also employ tissue specific deletion of PLXNC1 to describe its impact on leukocyte recruitment, tissue inflammation, platelet-neutrophil complex formation and the extent of myocardial IR injury. This will provide novel evidence into the role of the Sema7A PLXNC1 receptor ligand pair during conditions associated with leukocyte recruitment, tissue inflammation and IR. Future therapies for myocardial IR injury and several other conditions associated might be based on these findings.