MMP-9 Roles in the Aging Myocardial Response to Ischemia

描述（由申请人提供）： 心肌梗死（MI），即使采用当前的再灌注策略，仍然是心力衰竭的主要原因。识别MI后诱导不良心脏重塑的事件将提供预防、减缓或逆转心力衰竭进展的治疗靶点。一个主要危险 对MI反应不良的因素是年龄。随着年龄的增长，巨噬细胞向左心室（LV）的浸润增加，这刺激了细胞外基质（ECM）的积累，并导致LV功能发生微妙但显著的变化，表现为早期（E）至晚期（A）充盈率降低。MI后，巨噬细胞浸润和ECM积累是驱动事件，基质金属蛋白酶（MMP）-9调节这两个过程。MMP-9缺失减弱心脏对衰老的反应，部分是通过将巨噬细胞极化从促炎M1状态转变为抗炎M2状态。我们的初步数据表明，MMP-9水平在MI后第7天在老年小鼠中大大增加，MMP-9的这种增加产生更多的M1巨噬细胞，以延长炎症反应并延迟愈合期。MMP-9缺失恢复M1和M2极化平衡。 该更新提议将解决以下中心假设：在衰老小鼠的MI反应期间，MMP-9增强促炎性M1极化并减弱抗炎性M2极化以诱导不良重塑。 为了检验我们的假设，我们将测定年轻（3-6月龄）和老年（18-23月龄）野生型和MMP-9缺失小鼠中的巨噬细胞极化动力学。我们将评估MMP-9如何激活巨噬细胞极化以及该过程如何随着衰老而改变（目的1），年轻的心脏是否可以通过刺激M1巨噬细胞极化转换为老年表型（目的2），以及老年心脏是否可以通过刺激M2巨噬细胞极化转换为年轻表型（目的3）。这项建议是独一无二的，因为大多数研究使用MMP-9作为输出测量，我们将使用MMP-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，以进一步推进对MI后LV重塑起源的机制理解，并为转化研究提供靶点。这些研究结果对老年退伍军人群体具有重要意义。

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.