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

点击翻译按钮获取中文摘要

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.