MMP-9 Roles in the Aging Myocardial Response to Ischemia

摘要 心肌梗死(MI)，即使在目前的再灌注策略下，仍然是心脏的主要原因 失败了。心肌梗死后刺激左心室(LV)不良重塑的事件的识别， 因此，将提供治疗靶点来预防、减缓或逆转心力衰竭的进展。一位少校 对心肌梗死反应差的危险因素是年龄。我们观察到，在没有心脏老化的情况下 病理，诱导巨噬细胞进入左心室(LV)，增加基质金属蛋白酶-9 血浆和左室血中(MMP9)水平降低，成纤维细胞功能降低，左心室结构改变，左心室缩小 功能。心肌梗死后，细胞外基质(ECM)重塑是一个驱动事件，并初步分析了基质 金属蛋白酶-9(MMP9)在重塑中的作用提示，这种特殊的MMPs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是 在MI前和MI后的设置中都可能存在相关性。因此，这个项目的目标是理解 衰老对心肌梗死后细胞外基质、成纤维细胞和巨噬细胞反应的影响。这项提议将集中在澄清 对这一假说进行批判性检验的独特的基质金属蛋白酶-9驱动的机制是，衰老导致基线 增加基质金属蛋白酶-9和细胞外基质水平，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MMP9缺失的小鼠，我们将确定哪些MMP9介导的事件对LV影响最大 改建。 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(AIM 3)调节心肌梗死的反应。这一建议是独一无二的，因为大多数研究都使用 作为一种输出测量，只确定水平是否随刺激而变化，而不是 该酶如何调节细胞外基质重塑。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进一步推进机制 了解心肌梗死后左室重构的起源，为翻译研究提供靶点。这个 这些研究的结果将阐明衰老对心肌梗死后重塑的影响。

Abstract 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.