Myocardial Protection and Matrix Proteases

描述(申请人提供)：冠状动脉疾病可导致较长时间的心肌血流量减少(缺血)，从而导致心肌梗死(MI)。然而，矛盾的是，在长时间的缺血后重新建立血流；称为缺血-再灌注(I/R)，本身可以引起导致左心功能障碍的病理过程。此外，既往存在心肌梗死并经历第二次I/R事件的患者发生左心功能不全、发病率和死亡率的风险要大得多。随着I/R和MI的发生，细胞外蛋白水解酶、基质金属蛋白酶(MMPs)释放增加。最近，我们已经证明了一种独特的膜特异性基质金属蛋白酶-1型基质金属蛋白酶(MT1-MMP)在患者的心脏成纤维细胞和心肌细胞中大量表达，并在I/R后增加。此外，我们的初步结果证实，MT1-MMP的过度表达可以加重I/R损伤。该项目的中心假设是，在I/R时，间质MT1-MMP活性增加，这取决于蛋白激酶(PKC)信号通路的特定亚型。此外，在现有心肌梗死的情况下，MT1-MMP诱导增强发生在残存的存活心肌中，导致I/R第二次发作后整体MMP活性的启动效应，并直接导致左心功能不全。我们已经建立了一个与临床相关的猪I/R模型，并将利用该系统实现以下目标。(1)证实间质MT1-MMP活性升高与局部心功能不全的关系，这种关系是PKC亚型依赖的。(2)证明在限定的MI后，增强的MT1-MMPs的诱导和激活发生在远端存活的心肌中--这将在第二个I/R时期加剧局部左室收缩。(3)证明MT1-MMPs表达的局部改变将直接影响I/R后的局部收缩。这些综合研究的结果将是在I/R背景下确定导致左心功能障碍的独特的细胞外机制，特别是关注先前MI的临床相关情况，并确定将中断这一过程的特定和新的治疗靶点。 与公共卫生相关：在这个国家，死亡和残疾的最常见原因之一是心脏病发作；心肌损伤。我们已经证实，一种特定的膜结合酶在心脏病发作后上调。我们的目的是了解这种膜酶水平的增加如何导致心脏病发作后的不良结局，更重要的是开发调节这种酶的策略。这些结果将有助于为心脏病发作后心力衰竭患者开发新的测试和治疗方法。

DESCRIPTION (provided by applicant): Coronary artery disease can cause a prolonged period of reduced myocardial blood flow (ischemia) resulting in myocardial infarction (MI). However, paradoxically, re-establishing blood flow following a prolonged period of ischemia; termed ischemia-reperfusion (I/R), can in and of itself evoke a pathological process leading to LV dysfunction. Furthermore, patients with a pre-existing MI, which undergo a second I/R event are at much greater risk for LV dysfunction, morbidity and mortality. Increased release of the extracellular proteolytic enzymes, the matrix metalloproteinases (MMPs) occur with I/R and MI. Recently, we have demonstrated that a unique membrane specific MMP, the membrane type-1 MMP (MT1-MMP), is robustly expressed in cardiac fibroblasts and myocytes from patients, and is increased following I/R. Furthermore, our initial results have established that over- expression of MT1-MMP can exacerbate I/R injury. The central hypothesis of this project is that with I/R, increased interstitial MT1-MMP activity occurs which is dependent upon specific isoforms of the protein kinase (PKC) signaling pathway. Moreover, in the context of an existing MI, enhanced MT1- MMP induction occurs in the residual, viable myocardium causing a priming effect on overall MMP activity following a second episode of I/R, and directly contributes to LV dysfunction. We have developed a clinically relevant porcine model of I/R and will utilize this system to achieve the following aims. (1) Demonstrate a relationship between increased interstitial MT1-MMP activation and regional LV dysfunction which is PKC isoform dependent. (2) Demonstrate that enhanced MT1-MMP induction and activation occurs within the remote, viable myocardium following a defined MI- which will exacerbate regional LV contractility with a second period of I/R. (3) Demonstrate that regional modification of MT1-MMP expression will directly affect regional contractility following I/R. The outcome from these integrated studies will be to identify a unique extracellular mechanism contributing to LV dysfunction in the context of I/R with a particular focus on the clinically relevant condition of a previous MI and identify specific and novel therapeutic targets which will interrupt this process. PUBLIC HEALTH RELEVANCE: One of the most common causes of death and disability in this country is from a heart attack; damage to the heart muscle. We have identified that a specific membrane bound enzyme is upregulated following a heart attack. Our intention is to understand how increased levels of this membrane enzyme can contribute to poor outcomes following a heart attack, and more importantly develop strategies to regulate this enzyme. These results will help develop new tests and treatments for patients suffering from heart failure after a heart attack.