Effects of Cardiac Denervation on Ischemic Protection

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。项目1涉及对心脏保护机制的研究。 慢性器质性清醒猪的第二个缺血保护窗。独一无二的 这个项目的一个方面是使用大型哺乳动物模型，它类似于人类的病理生理学 比啮齿动物更接近，缺乏预先形成的冠脉侧支血管，心脏足够大到 提供区域功能、血流、生化、分子生物学和病理学的测量 缺血区和对侧偏远非缺血区的相同动物。该项目是 部分基于一种新的观察结果，即局部心脏去神经或肾上腺素能受体 封锁剥夺了第二个保护窗口。有三个主要假设：a)SWOP是 严重依赖交感神经系统；B)局部心脏去神经改变SWOP 远程、非缺血区；C)SWOP导致长链脂肪酸(LCFA)在 缺血，可能是由于AMP激酶升高，这种影响在清醒状态下SWOP后被消除 有局部心脏失神经的猪。项目1与其他项目和核心以及 该项目的主要主题是：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)整体心血管 研究。该项目还与项目2密切相关，该项目还研究了慢性仪器 猪模型，但在项目2中，模型是一种重复性顿抑(心肌冬眠)。的确， 项目1和项目2的几个目标是相同的，因为这两个项目将解决几个相同的目标 在两个不同的模型中的问题。项目1与项目3在分子信号和 凋亡的机制，与项目4特别是与H11激酶有关，它将被应用于 猪心脏局部失神经，以确定H11激酶是否能恢复心脏保护 神经丧失。项目1还利用了所有核心。

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. Project 1 involves the study of the mechanisms of cardiac protection in the second window of ischemic protection (SWOP) in chronically instrumented conscious swine. One unique aspect of this Project is the use of the large mammalian model, which 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. The project is based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor blockade abrogates the second window of protection. There are three major hypotheses: A)SWOP is critically dependent on the sympathetic nervous system; B)Regional cardiac denervation alters SWOP in the remote, non-ischemic zone; C)SWOP results in enhanced long chain fatty acid (LCFA) oxidation during ischemia, potentially due to AMP kinase elevation, an effect which is abolished following SWOP in conscious pigs with regional cardiac denervation. Project 1 is tied closely to the other projects and cores, as well as to the major themes of the Program Project, which are: 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 also linked closely to Project 2, which also studies the chronically instrumented swine model, but in Project 2 the model is one of repetitive stunning (myocardial hibernation). Indeed, several of the aims are shared by Projects 1 and 2, since the two projects will address several of the same questions in the two different models. Project 1 interacts with Project 3 in terms of molecular signaling and mechanisms of apoptosis, and with Project 4 particularly related to H11 kinase, which will be administered to pigs with regional cardiac denervation, to determine if H11 kinase can restore protection after cardiac denervation. Project 1 also utilizes all of the Cores.