The Role of Macrophage-derived MMPs in LV Remodeling

描述（由申请人提供）：尽管目前的治疗策略可以恢复缺血心肌的血流并限制梗死面积，但进展为充血性心力衰竭（CHF）的不良左心室（LV）重塑仍然是心肌梗死（MI）后的一个重要并发症。 细胞外基质（ECM）是MI后重塑过程中的关键组分，并且在梗死区域中发生胶原蛋白的增加以取代坏死的肌细胞并形成瘢痕。 巨噬细胞是一种慢性炎性细胞，其在MI后的愈合期期间介导LV重塑。 巨噬细胞是基质金属蛋白酶（MMP）的关键生产者和反应者，MMP是一种在重塑过程中调节基质周转的酶家族。 几个实验室已经证明MMP参与重塑事件，并且特定MMP（特别是MMP-9）的抑制或靶向缺失在MI后具有有益效果。 因此，了解巨噬细胞和巨噬细胞衍生的MMPs-7和-9如何调节基质介导的心肌梗塞愈合过程将有助于深入了解LV重塑的机制。 此外，越来越多的非基质调节MMP蛋白水解的概念表明，主要MMP功能可能是基质无关的。 在具体目标1中，我们将使用靶向删除单核细胞趋化蛋白-1（MCP-1）的小鼠研究巨噬细胞在早期LV重塑中的作用。 这一目标将扩大初步的工作表明，在梗死重塑的巨噬细胞的关键作用。 具体目标2将检查巨噬细胞特异性MMP-7和MMP-9过表达对巨噬细胞功能和重塑事件的功能作用。 最后，在具体目标3中，我们将使用新兴的蛋白质组学技术来鉴定巨噬细胞中可能在LV重塑中发挥作用的新型非基质MMP底物。

DESCRIPTION (provided by applicant): Despite current therapeutic strategies to restore blood flow to the ischemic myocardium and limit infarct size, adverse left ventricular (LV) remodeling that progresses to congestive heart failure (CHF) remains a significant complication following myocardial infarction (MI). The extracellular matrix (ECM) is a key component in the remodeling process following an MI, and increases in collagen occur in the infarct area to replace necrotic myocytes and form a scar. The macrophage is a chronic inflammatory cell that mediates LV remodeling during the healing phase post-Ml. Macrophages are key producers of and reactors to matrix metalloproteinases (MMPs), a family of enzymes that regulate matrix turnover during this remodeling process. Several laboratories have demonstrated MMP participation in remodeling events, and inhibition or the targeted deletion of specific MMPs (particularly MMP-9) have beneficial effects following MI. Thus, an understanding of how macrophages and macrophage-derived MMPs -7 and -9 regulate the matrix-mediated healing process in response to an MI will provide insight into the mechanisms of LV remodeling. In addition, the growing concept of non-matrix regulated MMP proteolysis illustrates that primary MMP functions may be matrix-independent. In Specific Aim 1, we will study the role(s) of macrophages in early LV remodeling using mice with a targeted deletion of monocyte chemotactic protein-1 (MCP-1). This aim will expand on preliminary work demonstrating a critical role for the macrophage in infarct remodeling. Specific Aim 2 will examine the functional role of macrophage-specific overexpression of MMP-7 and MMP-9 on macrophage functions and remodeling events. Finally, in Specific Aim 3, we will use the emerging technology of proteomics to identify novel non-matrix MMP substrates in the macrophage that may play a role in LV remodeling.