Myocardial Protection and Matrix Proteases

描述（由申请人提供）：冠状动脉疾病可引起长时间的心肌血流量减少（缺血），导致心肌梗死（MI）。然而，矛盾的是，在长时间缺血后重建血流；称为缺血-再灌注（I/R），其本身可引起导致左室功能障碍的病理过程。此外，先前存在心肌梗死的患者，如果发生第二次I/R事件，其左室功能障碍、发病率和死亡率的风险要大得多。细胞外蛋白水解酶，基质金属蛋白酶（MMPs）的释放增加发生在I/R和MI。最近，我们已经证明了一种独特的膜特异性MMP，膜1型MMP (MT1-MMP)，在患者的心脏成纤维细胞和肌细胞中强烈表达，并且在I/R后增加。此外，我们的初步结果已经确定，MT1-MMP的过表达会加剧I/R损伤。该项目的中心假设是，随着I/R，间质MT1-MMP活性的增加取决于蛋白激酶（PKC）信号通路的特定亚型。此外，在已有心肌梗死的情况下，残余存活心肌的MT1- MMP诱导增强，导致第二次I/R发作后整体MMP活性的启动效应，并直接导致左室功能障碍。我们已经开发了临床相关的猪I/R模型，并将利用该系统实现以下目标。(1)证明间质MT1-MMP激活增加与区域左室功能障碍之间的关系，这是PKC亚型依赖的。(2)证明MT1-MMP诱导和激活的增强发生在心肌梗死后的远端存活心肌中，这将在第二次I/R期加剧局部左室收缩力。(3)证明MT1-MMP表达的区域修饰会直接影响I/R后的区域收缩性。这些综合研究的结果将是确定在I/R背景下导致左室功能障碍的独特细胞外机制，特别关注先前心肌梗死的临床相关情况，并确定将中断这一过程的特定和新的治疗靶点。

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.