Myocardial Protection and Matrix Proteases

心肌保护和基质蛋白酶

• 批准号: 8653132
• 负责人: FRANCIS G SPINALE
• 金额: $ 32.28万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653132
• 关键词: Address; Affect; Animal Model; Binding; Biological; Blood flow; Cardiac; Cause of Death; Coronary Arteriosclerosis; Country; Enzymes; Event; Extracellular Matrix; Failure; Family suidae; Fibroblasts; Functional disorder; Healed; Heart failure; Intention; Interruption; Ischemia; Lentivirus Vector; Matrix Metalloproteinases; Measures; Mediating; Membrane; Methods; Microdialysis; Modeling; Modification; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Outcome; Pathologic Processes; Pathway interactions; Patients; Peptide Hydrolases; Phosphorylation; Play; Process; Protein Isoforms; Protein Kinase; Protein Kinase C; Pump; Reperfusion Injury; Reperfusion Therapy; Residual state; Risk; Signal Pathway; Signal Transduction; Structure; System; Testing; clinically relevant; disability; extracellular; healing; human MMP14 protein; interstitial; mortality; new therapeutic target; public health relevance; trafficking

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.

描述（由申请人提供）：冠状动脉疾病可导致心肌血流量长时间减少（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建血流;称为缺血-再灌注（I/R），其本身可以引起导致LV功能障碍的病理过程。此外，患有既存MI的患者，经历第二次I/R事件，LV功能障碍、发病率和死亡率的风险更高。细胞外蛋白水解酶，基质金属蛋白酶（MMPs）的释放增加与I/R和MI有关。最近，我们已经证明，一种独特的膜特异性MMP，膜1型MMP（MT 1-MMP），在心脏成纤维细胞和心肌细胞从患者中强烈表达，并增加I/R。此外，我们的初步结果已经确定，MT 1-MMP的过度表达可以加重I/R损伤。该项目的中心假设是，随着I/R，增加的间质MT 1-MMP活性发生，这取决于蛋白激酶（PKC）信号通路的特定亚型。此外，在现有MI的情况下，增强的MT 1- MMP诱导发生在残余的存活心肌中，导致在第二次I/R发作后对总体MMP活性的引发效应，并直接导致LV功能障碍。我们已经开发了一种临床相关的猪I/R模型，并将利用该系统实现以下目标。(1)证明间质性MT 1-MMP活化增加与PKC亚型依赖性局部LV功能障碍之间的关系。(2)证明在明确的MI后，远端存活心肌内发生了增强的MT 1-MMP诱导和激活-这将加剧第二个I/R期的局部LV收缩力。(3)证明MT 1-MMP表达的局部改变将直接影响I/R后的局部收缩力。这些综合研究的结果将是确定在I/R背景下导致LV功能障碍的独特细胞外机制，特别关注既往MI的临床相关状况，并确定将中断该过程的特异性和新型治疗靶点。