Ischemia/Reperfusion injury and Myocardial edema

缺血/再灌注损伤和心肌水肿

• 批准号: 10718260
• 负责人: Michael Simons
• 金额: $ 61.03万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718260
• 关键词: Acute; Acute myocardial infarction; Adherence; Affect; Affinity; Angiogenesis Inhibitors; Animal Model; Arrhythmia; BAY 54-9085; Binding; Biological; Blocking Antibodies; Blood flow; Brain; Cardiac Output; Cardiovascular Pathology; Chronic; Chronic Phase; Coronary; Data; Defect; Development; Edema; Electrophysiology (science); Endothelial Cells; Endothelium; Epidemic; Event; Extracellular Matrix; Fibrosis; Genetically Engineered Mouse; Goals; Hand; Heart; Heart Injuries; Heart failure; Hemorrhage; Human; Hypokalemia; Immunoglobulin G; Incidence; Infarction; Inflammation; Inflammatory; Injury; Ischemia; KDR gene; Kinetics; Knock-out; Lead; Left Ventricular Dysfunction; Link; Liquid substance; Lymphatic function; Maintenance; Malignant Neoplasms; Membrane; Molecular; Monoclonal Antibodies; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial dysfunction; Organ; Outcome; Pathogenesis; Permeability; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Production; Protein Dephosphorylation; Public Health; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Role; Safety; Severities; Signal Transduction; Site; Structure; Therapeutic; Time; Translating; Translations; Validation; Vascular Endothelial Growth Factors; Vascular Permeabilities; Ventricular Arrhythmia; Ventricular Tachycardia; acute stroke; bevacizumab; blocking factor; cadherin 5; fibroglycan; heart function; human monoclonal antibodies; improved; in vivo; interstitial; microCT; mutant; myocardial infarct sizing; novel; novel strategies; pre-clinical; preservation; prevent; receptor; response; sudden cardiac death; systemic inflammatory response; vascular endothelium permeability; wound healing; wound injury

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.

项目摘要 不受控制的炎症是急性和慢性心血管病理学的关键驱动因素。 然而，伴随的水肿是炎症的四个主要症状之一， 塞尔苏斯和盖伦两千年前，是知之甚少，往往被忽视的机械 水平然而，大量的证据表明其在缺血再灌注损伤（IRI）中的因果作用， 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），一直被视为 与虹膜相关的水肿发展的组成部分。有许多药物能够 阻断VEGF信号传导，包括广泛用作抗- 血管生成性癌症和眼科药物如贝伐单抗、索拉非尼、舒尼替尼和 帕唑帕尼等。然而，它们都不能用于急性/慢性缺血， 由于血管系统的诱导损失， 来自我们实验室的令人兴奋的新数据表明，选择性阻断VEGF是可能的， 诱导的磁导率缺陷，而不影响其信号的其他方面，从而消除 非选择性抗VEGF疗法的抗血管生成作用。在初步研究中， VEGF阻断性水肿形成可使心肌梗死面积缩小约50% 保护左室收缩和舒张功能，抑制室性心动过速。与 这些初步结果在手，我们建议检查功能的影响，心肌 水肿，并评估抗水肿治疗在这种情况下的效果。