Molecular Mechanisms in Chronically Stunned Myocardium

慢性顿抑心肌的分子机制

• 批准号: 7297793
• 负责人: STEPHEN F VATNER
• 金额: $ 30.48万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297793
• 关键词: autophagy; biological models; biological signal transduction; cardiovascular disorder prevention; chronic disease /disorder; disease /disorder model; gene expression; intracellular; ischemic preconditioning; model design /development; myocardial ischemia /hypoxia; swine

The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated, irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of the Project is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will be accomplished by utilizing an integrative approach including cellular and molecular studies as well as integrative whole animal physiology. This Project is based on a model of repetitive stunning in the swine, developed in the current funding period, that reproduces the chronic myocardial dysfunction with maintained viability that characterizes the human hibernating myocardium. We show in the Preliminary Data that the well defined cardioprotective mechanisms attributed to the first and second window of preconditioning are not activated in the model of repetitive stunning. Rather, in this model, cardiac protection results from the activation of a different gene/protein program of cell survival, and also from the regulation of specific intracellular pathways, including autophagy. Accordingly, this may represent a third window of protection. The goal of this proposal is to better define the mechanisms of cardioprotection activated in this model of repetitive stunning, to determine their durability, to compare those mechanisms with those activated during preconditioning, and to determine whether the repetition of ischemia extends this cardioprotection to the remote, normal myocardium. Importantly, the swine model of repetitive stunning resembles pathophysiology in humans more closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large to provide measurements of regional function, blood flow, biochemistry, molecular biology and pathology from the same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. This project is tied closely to the other projects and cores, as well as to the major themes of the Program Project: 1)Mechanisms of myocardial ischemia and reperfusion; 2)Molecular signaling; 3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascular research. This project is linked closely to Project 1, which also studies the chronically instrumented swine model, but in Project 1 the model is one of regional cardiac denervation. Indeed, several of the aims are shared by Projects 1 and 2, using two different models. It will be critical to compare the cellular/molecular alterations in Projects 1 and 2 to derive an understanding of the differences between the second and potentially, third window of protection. Project 2 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and with Project 4 particularly related to H11 kinase and its role in the protection afforded by chronic, repetitive stunning. Project 2 also utilizes all of the Cores.

心脏病最常见的形式是心肌缺血，其特征在于心肌缺血不充分。 由于冠状动脉阻塞，血液、基质和氧气供应到心脏。如果不治疗， 心肌梗塞（心脏病发作）形式的不可逆损伤。项目的总体目标 是确定缺血性心脏病的基本机制， 通过利用综合方法（包括细胞和分子研究以及 整体动物生理学。这个项目是基于猪的重复性昏迷模型， 在当前资助期内开发的，再现了慢性心肌功能障碍， 这是人类冬眠心肌的特征。我们在初步数据中显示， 归因于预处理的第一和第二窗口的定义的心脏保护机制不是 在重复性昏迷模型中被激活。相反，在这个模型中，心脏保护来自于 激活不同的基因/蛋白质程序的细胞存活，也从特定的调控 细胞内途径，包括自噬。因此，这可能是第三个保护窗口。 该提案的目的是更好地定义在这种模型中激活的心脏保护机制。 重复电击，以确定其耐久性，将这些机制与在电击期间激活的机制进行比较 预处理，并确定重复缺血是否将这种心脏保护扩展到 远端正常心肌重要的是，重复性昏迷的猪模型类似于病理生理学 在人类中比啮齿动物更接近，缺乏预先形成的冠状动脉侧支血管，心脏 足够大以提供区域功能、血流、生物化学、分子生物学的测量 以及缺血区和对侧、远端、非缺血区中相同动物的病理学 区该项目与其他项目和核心项目以及 项目内容：1）心肌缺血再灌注机制; 2）分子信号转导; 3)心肌保护和细胞存活与细胞死亡; 4）心血管研究的整合。这个项目是 与项目1密切相关，项目1也研究了慢性器械猪模型，但在项目1中， 模型是局部心脏去神经支配模型。事实上，项目1和项目2有几个共同的目标， 使用两种不同的模型。比较项目1和项目2中的细胞/分子改变至关重要 了解第二个保护窗口与可能的第三个保护窗口之间的区别。 项目2在分子信号传导和凋亡机制方面与项目3相互作用， 项目4特别涉及H11激酶及其在慢性、重复性和慢性炎症中提供的保护作用。 漂亮项目2也使用了所有的核心。