MMP-9 Roles in the Aging Myocardial Response to Ischemia

MMP-9 在衰老心肌缺血反应中的作用

• 批准号: 8397507
• 负责人: MERRY L LINDSEY
• 金额: --
• 依托单位: G V SONNY MONTGOMERY VA MEDCIAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397507
• 关键词: Address; Age; Aged, 80 and over; Aging; Automobile Driving; Back; Biochemistry; Biological Assay; Blood Pressure; Blood Vessels; Cardiac; Cause of Death; Cell physiology; Cellular biology; Cicatrix; Conditioned Culture Media; Development; Diagnosis; Discipline; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Protein Gene; Extracellular Matrix Proteins; Fibroblasts; Functional disorder; Gelatinase B; Genes; Goals; Grant; Heart; Heart failure; Histology; Human; Hypertension; Infarction; Infiltration; Inflammatory; Injury; Ischemia; Knockout Mice; Laboratories; Left Ventricular Remodeling; Left ventricular structure; Link; Macrophage Activation; Matrix Metalloproteinases; Measurement; Mediating; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Necrosis; Output; Oxygen; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiology; Plasma; Production; Protein Biosynthesis; Proteomics; Reperfusion Therapy; Risk Factors; Role; Signal Transduction; Stimulus; Structure; Testing; Therapeutic; Translational Research; United States; Validation; Ventricular Remodeling; Veterans; age group; age related; cell type; clinically relevant; cytokine; extracellular; functional decline; gene synthesis; improved; in vivo; innovation; macrophage; middle age; mortality; prevent; protein degradation; public health relevance; response; senescence; therapeutic target

DESCRIPTION (provided by applicant): Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. The identification of events that stimulate adverse remodeling of the left ventricle (LV) post-MI, therefore, will provide therapeutic targets to prevent, slow, or reverse the progression to heart failure. A major risk factor for a poor response to MI is age. We have observed that cardiac aging, in the absence of pathology, induces macrophage infiltration into the left ventricle (LV), increases matrix metalloproteinase-9 (MMP-9) levels in the plasma and the LV, decreases fibroblast function, alters LV structure, and diminishes LV function. Post-MI, extracellular matrix (ECM) remodeling is a driving event, and intial analysis of matrix metalloproteinase-9 (MMP-9) functions in remodeling suggest that this particular MMP predominantly influences extracellular signaling, ECM protein turnover, and fibroblast functions. MMP-9, therefore, is potentially relevant in both the pre- and post-MI settings. The goal of this project, accordingly, is to understand the role of aging on ECM, fibroblast, and macrophage responses to MI. This proposal will focus on elucidating unique MMP-9 driven mechanisms to critically test the hypothesis is that aging induces a baseline increase in MMP-9 and ECM levels, which alters ECM, fibroblast, and macrophage responses to MI. Using wild type and MMP-9 null mice, we will determine which MMP-9 mediated events most influence LV remodeling. To test our hypothesis, we will determine how ECM patterns (aim 1), fibroblast function (aim 2), and macrophage phenotypes (aim 3) regulate the MI response. This proposal is unique because most studies use MMP-9 as an output measurement and only determine whether levels change in response to a stimulus, not how the enzyme regulates ECM remodeling. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomic, and histological approaches to further advance the mechanistic understanding of the origins of post-MI LV remodeling and provide targets for translational research. The results of these studies will clarify the consequences of aging on post-MI remodeling.

描述（由申请人提供）： 即使采用目前的再灌注策略，心肌梗塞（MI）仍然是心力衰竭的主要原因。因此，识别心肌梗死后刺激左心室 (LV) 不良重塑的事件将为预防、减缓或逆转心力衰竭的进展提供治疗目标。心肌梗死反应不佳的一个主要危险因素是年龄。我们观察到，在没有病理的情况下，心脏衰老会诱导巨噬细胞浸润到左心室 (LV)，增加血浆和 LV 中的基质金属蛋白酶 9 (MMP-9) 水平，降低成纤维细胞功能，改变 LV 结构，并削弱 LV 功能。 MI 后，细胞外基质 (ECM) 重塑是一个驱动事件，对基质金属蛋白酶 9 (MMP-9) 在重塑中的功能的初步分析表明，这种特殊的 MMP 主要影响细胞外信号传导、ECM 蛋白周转和成纤维细胞功能。因此，MMP-9 在 MI 前后的情况下都可能具有相关性。因此，该项目的目标是了解衰老对 ECM、成纤维细胞和巨噬细胞对 MI 反应的作用。该提案将重点阐明独特的 MMP-9 驱动机制，以严格检验以下假设：衰老会导致 MMP-9 和 ECM 水平基线增加，从而改变 ECM、成纤维细胞和巨噬细胞对 MI 的反应。使用野生型和 MMP-9 缺失小鼠，我们将确定哪些 MMP-9 介导的事件最影响左心室重塑。为了检验我们的假设，我们将确定 ECM 模式（目标 1）、成纤维细胞功能（目标 2）和巨噬细胞表型（目标 3）如何调节 MI 反应。该提议是独特的，因为大多数研究使用 MMP-9 作为输出测量，并且仅确定水平是否响应刺激而变化，而不是确定酶如何调节 ECM 重塑。我们的多方面方法包括体内生理学、细胞生物学、生物化学、蛋白质组学和组织学方法，以进一步推进对心肌梗死后左心室重塑起源的机制理解，并为转化研究提供目标。这些研究的结果将阐明衰老对心肌梗死后重塑的影响。