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是恢复缺血心肌的血流并限制梗死范围，但发展为充血性心力衰竭(CHF)的不良左室(LV)重构仍然是心肌梗死(MI)后的一个重要并发症。细胞外基质(ECM)是心肌梗死后重塑过程中的关键成分，梗死区胶原的增加取代了坏死的心肌细胞，形成了瘢痕。巨噬细胞是一种慢性炎症细胞，在ML后的愈合期参与左室重构。巨噬细胞是基质金属蛋白酶(MMPs)的关键生产者和反应者，MMPs是一种酶家族，在这个重塑过程中调节基质的周转。几个实验室已经证明了基质金属蛋白酶参与重塑事件，抑制或靶向缺失特定的基质金属蛋白酶(尤其是基质金属蛋白酶-9)对心肌梗死后有有益的影响。因此，了解巨噬细胞和巨噬细胞来源的MMPs-7和MMPs-9如何调节基质介导的心肌梗死愈合过程将有助于深入了解左室重构的机制。此外，越来越多的非基质调节的基质金属蛋白酶蛋白分解的概念表明，主要的基质金属蛋白酶的功能可能是非基质独立的。在特定的目标1，我们将研究巨噬细胞在单核细胞趋化蛋白-1靶向缺失的小鼠早期左室重构中的作用(S)。这一目标将在初步工作的基础上展开，展示巨噬细胞在脑梗塞重塑中的关键作用。特定目的2将研究巨噬细胞特异性过表达的基质金属蛋白酶-7和基质金属蛋白酶-9在巨噬细胞功能和重塑事件中的功能作用。最后，在特定的目标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左室重构中发挥作用的新的非基质基质。

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.