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。识别导致心肌梗死后不良心脏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。重大风险 对MI反应不佳的因素是年龄。随着年龄的增长，巨噬细胞渗入左心室(LV)，刺激细胞外基质(ECM)积聚，导致LV功能发生细微而显著的变化，表现为早期(E)和晚期(A)充盈比率降低。心肌梗死后巨噬细胞的浸润和细胞外基质的积聚是心肌梗死后的驱动因素，而基质金属蛋白酶-9对这两个过程均有调节作用。基质金属蛋白酶-9的缺失减弱了心脏对衰老的反应，部分原因是通过将巨噬细胞极化从促炎的M1状态转变为抗炎的M2状态。我们的初步数据显示，在老年小鼠心肌梗死后第7天，基质金属蛋白酶-9的水平显著升高，这种升高产生更多的M1巨噬细胞，以延长炎症反应和延迟愈合期。基质金属蛋白酶-9缺失可恢复M1和M2极化平衡。这项更新建议将解决这一中心假设，即在衰老小鼠的MI反应中，基质金属蛋白酶-9增强促炎M1极化和减弱抗炎M2极化以诱导不利的重塑。为了验证我们的假设，我们将测定年轻(3-6月龄)和老年(18-23月龄)野生型和MMP9缺失小鼠的巨噬细胞极化动力学。我们将评估基质金属蛋白酶-9如何激活巨噬细胞极化，以及这一过程如何随着年龄的增长而改变(目标1)，年轻心脏是否可以通过刺激M1巨噬细胞极化转换到旧表型(目标2)，以及老年心脏是否可以通过刺激M2巨噬细胞极化转换到年轻表型(目标3)。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，因此我们将使用基质金属蛋白酶-9作为主要输入。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。这些研究结果对老龄化的退伍军人群体具有较高的指导意义。

DESCRIPTION (provided by applicant): Myocardial infarction (MI), even with current reperfusion strategies, remains the leading cause of heart failure. Identifying the events that induce adverse cardiac remodeling post-MI will provide therapeutic targets to prevent, slow, or reverse progression to heart failure. A major risk factor for a poor response to MI is age. With age, there is an increased infiltration of macrophages into the left ventricle (LV), which stimulates extracellular matrix (ECM) accumulation and leads to a subtle but significant change in LV function evidenced by reduced early (E) to late (A) filling ratios. Post-MI, macrophage infiltration and ECM accumulation are driving events, and matrix metalloproteinase (MMP)-9 regulates both of these processes. MMP-9 deletion attenuates the cardiac response to aging, in part by shifting macrophage polarization from a pro-inflammatory M1 state to an anti- inflammatory M2 state. Our preliminary data demonstrate that MMP-9 levels are much increased in older mice at day 7 post-MI, and this in-crease in MMP-9 yields more M1 macrophages to extend the inflammatory response and delay the healing phase. MMP-9 deletion restores the M1 and M2 polarization balance. This renewal proposal will address the central hypothesis that during the MI response in aging mice, MMP-9 enhances pro-inflammatory M1 polarization and attenuates anti- inflammatory M2 polarization to induce adverse remodeling. To test our hypothesis, we will determine macrophage polarization kinetics in young (3-6 month old) and old (18-23 month old) wild type and MMP-9 null mice. We will evaluate how MMP-9 activates macrophage polarization and how this process is altered with aging (aim 1), whether young hearts can be switched to an old phenotype by stimulating M1 macrophage polarization (aim 2), and whether old hearts can be switched to a young phenotype by stimulating M2 macrophage polarization (aim 3). This proposal is unique, because most studies use MMP-9 as an output measurement whereby we will use MMP-9 as a major input. Our multi-faceted approach includes in vivo physiology, cell biology, biochemistry, proteomics, 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 have high significance for the aging veteran population.