Angiogenesis Protection Induced by sFRP3 Myocyte/Vascular Cross-Talk

项目摘要 在过去的半个世纪里，已经有数百项，如果不是数千项的研究， 代理商，但相对较少的进展到诊所。这种缺乏可能有几个原因。 翻译成功：1.识别这些潜在心脏保护机制的模型是基于 急性实验，不类似于慢性缺血患者; 2.许多现有的保护机制不能 诱导血管生成/动脉生成，这是慢性心肌缺血患者所需的， 冠状动脉血流;以及3.数据仅来自啮齿动物模型。当前应用程序基于 一种新的心脏保护剂sFRP 3的发现，这是在猪慢性 预处理虽然对心脏病中的这种基因知之甚少，但也发现它是 在心脏病患者中上调，这刺激了先前的研究得出结论，sFRP 3发挥了 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是不能改善 通过诱导血管生成/动脉生成使心肌血流向慢性缺血心脏。我们 初步数据表明，sFRP 3诱导血管生成和动脉生成，这使其成为一种新的血管生成因子。 重要的新机制，不仅为急性心脏保护，而且还保护慢性 心肌缺血性疾病，并最终将用于保护其他器官， 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：sFRP 3，当通过注射到心脏或遗传方式过度表达时， 通过诱导血管生成/动脉生成对冠状血管具有重要的保护作用。 假设B：sFRP 3诱导的对急性冠状动脉闭塞的保护作用是由新的 信号传导机制而不是血管生成/动脉生成。

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.