Effects of Cardiac Denervation on Ischemic Protection

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， 通过利用包括细胞和分子研究在内的综合方法以及 整体动物生理学。项目1涉及研究心脏保护机制， 第二个缺血保护窗口（SWOP）在慢性仪器清醒猪。一个唯一 该项目的一个方面是使用大型哺乳动物模型，该模型类似于人类的病理生理学 比啮齿类动物更接近，缺乏预先形成的冠状侧支血管，心脏足够大， 提供区域功能，血流，生物化学，分子生物学和病理学的测量， 缺血区和对侧、远端、非缺血区中的相同动物。该项目 部分基于新的观察结果，即区域心脏去神经支配或肾上腺素能受体 封锁取消了第二个保护窗口。有三个主要假设：A）SWOP是 严重依赖于交感神经系统; B）局部心脏去神经支配改变了SWOP， C）SWOP导致在缺血期间长链脂肪酸（LCFA）氧化增强; 缺血，可能是由于AMP激酶升高，这种作用在意识清醒的SWOP后被消除。 局部心脏去神经的猪。项目1与其他项目和核心密切相关， 本项目的主要内容是：1）心肌缺血和再灌注的机制; 2)分子信号传导; 3）心肌保护和细胞存活与细胞死亡; 4）整合性心血管 research.该项目也与项目2密切相关，项目2也研究了长期使用仪器的 猪模型，但在项目2中，模型是重复性顿抑（心肌冬眠）。的确， 项目1和项目2的一些目标是相同的，因为这两个项目将解决一些相同的问题， 两种不同模式的问题。项目1与项目3在分子信号传导方面相互作用， 细胞凋亡的机制，并与项目4，特别是有关H11激酶，这将是给药， 猪局部心脏去神经，以确定H11激酶是否可以恢复心脏后的保护作用， 去神经项目1也使用了所有的核心。

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. 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.