SFRP2, cell survival, and coronary vascular angiogenesis

描述（由申请人提供）：心肌缺血和冠状动脉疾病是美国死亡和残疾的最重要原因之一。尽管对缺血预处理的机制进行了深入研究，但仍难以将该有益过程转化为临床环境。一个限制是发现模型， 增强血管生成和侧支形成，这是保护缺血心肌的最有效方法，也是当前项目的核心。因此，我们开发了一种低流量冠状动脉狭窄重复发作的猪模型，该模型再现了缺血性心脏病患者中发现的短暂和重复缺血发作的情况，其通过血管生成显示侧支发展。秘密卷曲相关蛋白2（sFRP 2）被发现作为唯一的上调基因在这个模型中，表明这种蛋白质是潜在的一种新的介质的心脏保护所赋予的慢性缺血，发生在冠心病患者。我们的初步数据表明，sFRP 2的过度表达显着增加血管生成和侧支血流量，并减少急性心肌缺血的梗死面积。这种过表达还通过两种主要的新机制改善了永久性冠状动脉闭塞后的重塑过程，即通过未覆盖的内质网（ER）应激反应信号传导促进细胞存活，以及通过血管生成增加侧支血流。该资助提案的目标是通过使用转基因和敲除小鼠模型以及大型动物模型来研究sFRP 2保护心脏的机制。我们将首先测试我们的假设A，即心脏中sFRP 2的过表达将通过一种新的机制促进心脏细胞存活，该机制通过激活ATF 6/GRP 78信号转导增强对ER应激的反应。重要的是，我们将检验假设B，即sFRP 2通过2种机制保护慢性MI后的心脏重塑。第一种机制涉及诱导血管生成/动脉生成，第二种机制涉及通过激活ATF 6/GRP 78信号传导通过ER应激途径改善细胞存活。纤维化将是心脏重塑中的次要且不太重要的机制。显然，通过动脉生成和通过sFRP 2信号传导保护肌细胞的组合，定义这种途径的能力，从而潜在地支持损伤后的心肌修复，对于心肌梗死和心力衰竭的治疗具有巨大的临床影响，心肌梗死和心力衰竭是我们社会中死亡和残疾的主要原因。

DESCRIPTION (provided by applicant): Myocardial ischemia and coronary artery disease are among the most important causes of death and disability in the U.S. Despite the intense investigation of the mechanisms of ischemic preconditioning, it has been difficult to translate that beneficial process to the clinical setting. One limitation is to discover models that actually enhance angiogenesis and collateral formation, which is the most effective way of protecting ischemic myocardium, and which is central to the current project. Therefore, we developed a swine model of repetitive episodes of low-flow coronary stenosis, which reproduces the conditions of transient and repeated ischemic episodes found in patients with ischemic heart disease, which displays collateral development through angiogenesis. Secret frizzled related protein 2 (sFRP2) was found as the most up-regulated gene uniquely in this model, indicating that this protein is potentially a novel mediator of cardiac protection conferred by chronic ischemia, as occurs in patients with coronary disease. Our preliminary data indicate that over expression of sFRP2 significantly increases angiogenesis and collateral blood flow and reduces the size of infarctions in acute myocardial ischemia. This over expression also improves the remodeling process after permanent coronary artery occlusion through two major novel mechanisms, by promoting cell survival through an uncovered endoplasmic reticulum (ER) stress response signaling, and by increasing the collateral blood flow through angiogenesis. The goal of this grant proposal is to investigate the mechanisms involved in cardiac protection by sFRP2 by using both a transgenic and knockout mouse model as well as a large animal model. We will first test our Hypothesis A that over-expression of sFRP2 in the heart will promote cardiac cell survival through a novel mechanism by enhancing the response to ER stress via the activation of ATF6 /GRP78 signaling. Importantly, we will test Hypothesis B that sFRP2 protects cardiac remodeling after chronic MI through 2 mechanisms. The first mechanism involves induction of angiogenesis/arteriogenesis, and the second mechanism involves improved cell survival through the ER stress pathway via the activation of ATF6/GRP78 signaling, Fibrosis will be a secondary and less important mechanism in cardiac remodeling. Clearly the ability to define such pathways, and thus to potentially bolster myocardial repair after injury, through a combination of arteriogenesis and protection of the myocyte through sFRP2 signaling, has enormous clinical ramifications for the treatment of both myocardial infarction and heart failure, the leading causes of death and disability in our society.