Angiogenesis Protection Induced by sFRP3 Myocyte/Vascular Cross-Talk

sFRP3 肌细胞/血管交互作用诱导的血管生成保护

• 批准号: 9900045
• 负责人: STEPHEN F VATNER
• 金额: $ 56.45万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900045
• 关键词: Acute; Adverse effects; Angiogenic Factor; Blood Vessels; Blood flow; Cardiac; Cardiotonic Agents; Cerebrovascular Disorders; Chronic; Clinic; Clinical; Coronary; Coronary Occlusions; Coronary Vessels; Data; Development; Disease; Endothelial Cells; Failure; Family suidae; Genes; Grant; Growth Factor; HIF1A gene; Health; Heart; Heart Diseases; Heart failure; Injections; Ischemia; Malignant Neoplasms; Mediating; Modeling; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Proteins; Rodent Model; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Tissue Inhibitor of Metalloproteinase-1; Transgenic Model; Translations; Vascular Endothelial Growth Factors; angiogenesis; base; cardioprotection; clinical translation; coronary artery occlusion; deep sequencing; design; experimental study; frizzled related protein-3; gender difference; improved; novel; overexpression; preconditioning; protective effect; success

Project Summary Over the past half century there have been hundreds, if not thousands, of studies identifying cardioprotective agents, but relatively few have progressed to the clinics. There are probably several reasons for this lack of translational success: 1. That models identifying these potential cardioprotective mechanisms are based on acute experiments, not similar to chronic ischemia in patients; 2. many prior protective mechanisms cannot induce angiogenesis/arteriogenesis, which is required for patients with chronic myocardial ischemia and limited coronary blood flow; and 3. the data were derived solely from rodent models. The current application is based on the discovery of a novel cardioprotective agent, sFRP3, which was found in pigs with chronic preconditioning. Although relatively little is known about this gene in heart disease, it has been also found to be upregulated in patients with heart disease, which stimulated prior studies to conclude that sFRP3 exerted an adverse effect in heart failure, a conclusion diametrically opposed to our hypothesis and preliminary data. One of the major limitations to clinical translation of prior cardioprotective agents, is the inability to improve myocardial blood flow to the chronically ischemic heart by inducing angiogenesis/arteriogenesis. Our preliminary data indicate that sFRP3 induces both angiogenesis and arteriogenesis, which makes it an important new mechanism designed for not only acute cardioprotection, but also protects against chronic myocardial ischemic disease and finally will be of use to protect other organs where compromised blood flow induces disease, e.g., peripheral arterial and cerebral vascular disease. We will study 2 major hypotheses: Hypothesis A: sFRP3, when overexpressed either by injection into the heart, or genetically, exerts an important protective effect on coronary vessels, by induction of angiogenesis/arteriogenesis. Hypothesis B: sFRP3 induced protection against acute coronary artery occlusion is mediated by novel signaling mechanisms rather than angiogenesis/arteriogenesis.

项目概要 在过去的半个世纪中，已有数百甚至数千项研究确定了心脏保护作用 代理，但相对较少已经进展到诊所。造成这种缺乏的原因可能有几个 转化成功： 1. 识别这些潜在心脏保护机制的模型基于 急性实验，与患者慢性缺血不相似； 2.许多现有的保护机制不能 诱导血管生成/动脉生成，这是慢性心肌缺血和有限的患者所必需的 冠状动脉血流量； 3. 数据仅来自啮齿动物模型。当前的应用程序基于 发现一种新型心脏保护剂 sFRP3，该药物在患有慢性疾病的猪身上发现 预处理。尽管人们对这个基因在心脏病中的作用知之甚少，但也发现它与心脏病有关。 在心脏病患者中表达上调，这促使之前的研究得出结论，sFRP3 发挥了 对心力衰竭的不利影响，这一结论与我们的假设和初步数据截然相反。一 现有心脏保护剂临床转化的主要限制之一是无法改善 通过诱导血管生成/动脉生成，心肌血流流向慢性缺血的心脏。我们的 初步数据表明，sFRP3 可诱导血管生成和动脉生成，这使其成为一种 重要的新机制不仅可以保护急性心脏，还可以预防慢性心脏疾病 心肌缺血性疾病，最终将用于保护血流受损的其他器官 诱发疾病，例如外周动脉和脑血管疾病。我们将研究两个主要假设： 假设 A：当 sFRP3 通过注射到心脏或基因上过度表达时，会发挥 通过诱导血管生成/动脉生成，对冠状血管产生重要的保护作用。 假设 B：sFRP3 诱导的针对急性冠状动脉闭塞的保护作用是由新的介导的 信号传导机制而不是血管生成/动脉生成。