Ischemia/Reperfusion injury and Myocardial edema

项目摘要 不受控制的炎症是急性和慢性心血管病理的关键驱动因素。 然而，伴随而来的浮肿是炎症的四个主要征兆之一，由 赛尔苏斯和伽伦在两千年前，人们对其了解很少，在机械论上往往被忽视 水平。然而，大量证据表明，它在缺血再灌注损伤(IRI)和 心脏、大脑和其他器官的后遗症。 虽然许多分子可以诱导水肿形成，但血管内皮生长因子 血管内皮生长因子(VEGF)，又称血管通透性因子(VPF)，已被认为是 IRI相关的水肿发展的组成部分。有许多药物能够 阻断血管内皮生长因子信号，包括被广泛用作抗血管通透性的 血管生成癌和眼科药物，如贝伐单抗、索拉非尼、舒尼替尼和 帕佐帕尼和其他人。然而，它们都不能用于急性/慢性缺血。 由于诱导的血管系统丧失而造成的环境。 来自我们实验室的令人兴奋的新数据表明，选择性地阻断血管内皮生长因子是可能的。 诱导的渗透性缺陷，而不影响其信号的其他方面，从而消除 非选择性抗血管内皮生长因子治疗的抗血管生成作用。在初步研究中，阻止 血管内皮生长因子阻断水肿形成导致心肌梗死面积缩小~50% 保护左心室收缩和舒张期功能，抑制室速诱导性。使用 根据这些初步结果，我们建议检查心肌的功能效应 并评估在这种情况下抗浮肿疗法的效果。

Project Summary Uncontrolled inflammation is a key driver of acute and chronic cardiovascular pathology. However, the accompanying edema, one of the four cardinal signs of inflammation defined by Celsus and Galen two millennia ago, is poorly understood and often ignored at the mechanistic level. Yet ample evidence shows its causal roles in ischemia reperfusion injury (IRI) and resultant sequelae in the heart, brain, and other organs. While a number of molecules can induce edema formation, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) has been viewed as the key component of IRI-associated edema development. There are a number of drugs capable of blocking VEGF signaling, including vascular permeability that are widely used as anti- angiogenic cancer and ophthalmologic drugs such as bevacizumab, sorafenib, sunitinib and pazopanib among others. However, none of them can be used in acute/chronic ischemia settings due to the induced loss of blood vasculature. Exciting new data from our lab have demonstrated that it is possible to selectively block VEGF- induced permeability defects without affecting other aspects of its signaling, thereby eliminating anti-angiogenic effects of non-selective anti-VEGF therapies. In preliminary studies, blocking VEGF-blocking edema formation leads to a ~50% reduction in the size of myocardial infarction and preservation of LV systolic and diastolic function and suppression of VT inducibility. With these preliminary results in hand, we propose to examine the functional effects myocardial edema and evaluate the effect of anti-edema therapies in this setting.