Molecular Mechanisms in Chronically Stunned Myocardium

心脏病最常见的形式是心肌缺血，其特征是心脏供血不足。 由于冠状动脉阻塞，心脏的血液、基质和氧气的供应。如果不治疗， 不可逆转的损害以心肌梗死(心脏病发作)的形式接踵而至。该项目的总体目标 是确定对了解缺血性心脏病至关重要的机制，这将 通过使用包括细胞和分子研究以及 综合整体动物生理学。这个项目是基于猪的重复晕厥模型， 在当前资助期开发的，它再现了慢性心肌功能障碍并保持了 这是人类冬眠心肌的特征。我们在初步数据中显示，这口井 已定义的心肌保护机制归因于预适应的第一和第二窗口 在重复的眩晕模式下被激活。相反，在这个模型中，心脏保护是由 激活不同的基因/蛋白质程序对细胞的存活，也来自于特异性的调节 细胞内途径，包括自噬。因此，这可能代表着第三个保护窗口。 这项提议的目标是更好地定义在这一模型中激活的心脏保护机制 重复击晕，以确定它们的耐用性，将这些机制与在 预适应，并确定重复缺血是否将这种心脏保护扩大到 远端的正常心肌。重要的是，重复性眩晕的猪模型与病理生理学相似。 在人类中，比啮齿类动物更接近，缺乏预先形成的冠脉侧支血管，心脏 足够大以提供区域功能、血流、生化、分子生物学的测量 和病理来自缺血区和对侧的相同动物，遥远的，非缺血的 区域。该项目与其他项目和核心密切相关，并与 计划项目：1)心肌缺血和再灌注的机制；2)分子信号； 3)心肌保护和细胞存活与细胞死亡：4)心血管综合研究。这个项目是 与项目1密切相关，该项目也研究慢性仪器化猪模型，但在项目1中 模型是心脏局部失神经的一种。事实上，项目1和项目2有几个目标是相同的， 使用两种不同的模型。比较项目1和项目2中的细胞/分子变化将是至关重要的 以了解第二个保护窗口和可能的第三个保护窗口之间的区别。 项目2与项目3在分子信号和凋亡机制方面相互作用，并与 项目4特别涉及H11激酶及其在慢性、重复的 令人惊叹。项目2还利用了所有的核心。

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.