SFRP2, cell survival, and coronary vascular angiogenesis

描述(申请人提供)：心肌缺血和冠状动脉疾病是美国最重要的死亡和残疾原因之一。尽管对缺血预适应的机制进行了深入的研究，但很难将这一有益的过程转化为临床环境。一个限制是发现实际 促进血管生成和侧支循环形成，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，我们建立了一种重复发作的低流量冠状动脉狭窄的猪模型，该模型再现了缺血性心脏病患者中发现的短暂和反复缺血发作的情况，这种情况通过血管生成表现为侧支循环发展。秘密卷曲相关蛋白2(SFRP2)被发现是该模型中唯一上调最多的基因，表明该蛋白可能是慢性缺血所致心脏保护的一种新的介质，就像在冠心病患者中所发生的那样。我们的初步数据表明，在急性心肌缺血中，SFRP2的过度表达显著增加血管生成和侧支循环血流量，并缩小梗塞范围。这种过度表达还通过两个主要的新机制改善永久性冠状动脉闭塞后的重塑过程，即通过未被覆盖的内质网(ER)应激反应信号促进细胞存活，以及通过血管生成增加侧支血流量。这项拨款提案的目的是通过使用转基因和基因敲除小鼠模型以及大型动物模型来研究SFRP2参与心脏保护的机制。我们将首先验证我们的假设A，即在心脏中过表达SFRP2将通过一种新的机制通过激活ATF6/GRP78信号来增强对内质网应激的反应，从而促进心脏细胞的存活。重要的是，我们将检验假设B，SFRP2通过两种机制保护慢性心肌梗死后的心脏重构。第一个机制涉及诱导血管生成/动脉生成，第二个机制涉及通过激活ATF6/GRP78信号通路通过内质网应激途径改善细胞存活，纤维化将是心脏重塑中次要且不太重要的机制。显然，通过动脉形成和通过SFRP2信号保护心肌细胞相结合来确定这种途径，从而潜在地支持损伤后的心肌修复，对于治疗心肌梗死和心力衰竭具有巨大的临床意义，这两种疾病是我们社会中导致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.