SFRP2, cell survival, and coronary vascular angiogenesis

SFRP2、细胞存活和冠状血管生成

• 批准号: 8875747
• 负责人: Dorothy Eileen Vatner
• 金额: $ 45.27万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875747
• 关键词: Acute; Adverse effects; Angiogenic Factor; Animal Model; Apoptosis; Applications Grants; Area; Blood Vessels; Blood flow; Cardiac; Cause of Death; Cell Survival; Cessation of life; Chronic; Cicatrix; Clinical; Coronary; Coronary Arteriosclerosis; Coronary Stenosis; Coronary heart disease; Data; Development; Endothelial Cells; Family suidae; Fibrosis; GRP78 gene; Genes; Goals; Grant; Health; Heart; Heart failure; Heat-Shock Proteins 70; Hypertrophy; In Vitro; Infarction; Injury; Investigation; Ischemia; Ischemic Preconditioning; Knockout Mice; Left Ventricular Function; Mediating; Mediator of activation protein; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Pathway interactions; Patients; Process; Proteins; Regulation; Research; Risk; Signal Transduction; Smooth Muscle Myocytes; Societies; Stress; Stress Response Signaling; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; adverse outcome; angiogenesis; base; clinically relevant; connective tissue growth factor; coronary artery occlusion; disability; endoplasmic reticulum stress; heart dimension/size; human SFRP4 protein; improved; in vivo; innovation; mouse model; novel; overexpression; preconditioning; prevent; repaired; response

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.

描述（由申请人提供）：尽管对缺血性预处理的机制进行了严格的研究，但在美国，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，但很难将这种有益过程转化为临床环境。一个限制是发现实际上的模型 增强血管生成和附带形成，这是保护缺血性心肌的最有效方法，并且是当前项目的核心。因此，我们开发了一种低流量冠状动脉狭窄的重复发作的猪模型，该模型在缺血性心脏病患者中繁殖了瞬时和重复缺血性发作的条件，该病通过血管生成显示副作用。在该模型中发现了秘密毛躁相关蛋白2（SFRP2）是最上调的基因，表明该蛋白可能是慢性缺血赋予的新型心脏保护介质，就像冠状动脉疾病患者一样。我们的初步数据表明，SFRP2的表达显着增加了血管生成和附带血流，并减少了急性心肌缺血中梗塞的大小。这种过度表达还通过两种主要的新型机制在永久性冠状动脉闭塞后改善了重塑过程，通过通过未覆盖的内质网应力反应信号传导促进细胞存活，并通过增加血管生成的附加血液流动。该赠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心脏保护所涉及的机制。我们将首先检验我们的假设A，即心脏中SFRP2的过表达将通过一种新机制来促进心脏细胞的存活，通过通过ATF6 /GRP78信号传导的激活来增强对ER应力的反应。重要的是，我们将测试假设B，即SFRP2通过2种机制保护了慢性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ATF6/GRP78信号传导的激活通过ER应力途径改善细胞存活，纤维化将是心脏重塑的二次且不重要的机制。显然，通过动脉生成和通过SFRP2信号对心肌生成和保护心肌的保护结合，可以定义这种途径，从而定义这种途径，从而潜在地增强心肌修复，这具有巨大的临床后果，以治疗心肌梗死和心脏失败，这是我们社会的死亡和残障原因。