MMP-9 Roles in the Aging Myocardial Response to Ischemia

描述(由申请人提供)： 心肌梗死(MI)，即使在目前的再灌注策略下，仍然是心力衰竭的主要原因。因此，识别刺激心肌梗死后左室(LV)不利重构的事件将为预防、减缓或逆转心力衰竭的进展提供治疗靶点。对心肌梗死反应差的一个主要风险因素是年龄。我们观察到，心脏老化，在没有病理改变的情况下，诱导巨噬细胞进入左心室(LV)，增加血浆和LV中基质金属蛋白酶-9(MMP9)的水平，降低成纤维细胞功能，改变LV结构，降低LV功能。心肌梗死后，细胞外基质(ECM)重塑是一个驱动事件，对基质金属蛋白酶-9(MMP9)在重塑中作用的初步分析表明，这种特殊的基质金属蛋白酶主要影响细胞外信号、ECM蛋白周转和成纤维细胞功能。因此，基质金属蛋白酶-9在心肌梗死前和心肌梗死后的设置中都具有潜在的相关性。因此，该项目的目标是了解衰老对细胞外基质、成纤维细胞和巨噬细胞对心肌梗死的反应的作用。这项建议将集中于阐明独特的基质金属蛋白酶-9驱动的机制，以关键地检验这一假说，即衰老导致基质金属基质和细胞外基质水平的基线升高，从而改变细胞外基质、成纤维细胞和巨噬细胞对心肌梗死的反应。利用野生型和基质金属蛋白酶-9缺失的小鼠，我们将确定哪些基质金属蛋白酶-9介导的事件对左室重构的影响最大。为了验证我们的假设，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。这一建议是独一无二的，因为大多数研究使用基质金属蛋白酶-9作为输出测量，并且只确定水平是否随着刺激的反应而变化，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，以进一步促进对心肌梗死后左室重构起源的机制理解，并为翻译研究提供靶点。这些研究的结果将阐明衰老对心肌梗死后重构的影响。 公共卫生相关性： 心力衰竭是指心脏无法为身体提供足够的氧气，在美国是导致死亡的主要原因。在每年确诊的50,000名心力衰竭患者中，70%的人曾因心脏病发作(心肌梗死；MI)而心力衰竭。这项资助的主要目的是利用小鼠心肌梗死模型，了解衰老如何通过调节细胞外基质环境和两种细胞类型--成纤维细胞和巨噬细胞--影响瘢痕形成。

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. PUBLIC HEALTH RELEVANCE: Heart failure is the inability of the heart to adequately supply the body with oxygen and is a leading cause of death in the United States. Of the 50,000 heart failure patients diagnosed each year, 70% have heart failure due to a previous heart attack (myocardial infarction; MI). The main objective of this grant is to use a mouse MI model to understand how aging influences scar formation by regulating the extracellular matrix environment and two cell types, the fibroblast and macrophage.