Collagen-derived peptides to target inflammation in myocardial infarction

项目总结 心肌梗死(MI)会导致疤痕的产生，疤痕主要由心脏细胞外构成 矩阵(ECM)。ECM的降解和沉积之间的平衡是临床的一个强有力的预测指标 结果。基质金属蛋白酶(MMPs)引起细胞外基质的降解，细胞外基质的沉积通过 心脏成纤维细胞。细胞外基质的降解和沉积都促进了不利的重构和进展到心脏 失败了。在基质金属蛋白酶家族中，基质金属蛋白酶-9已被报道为心功能不全的预后指标。 心肌梗死(MI)患者，由于基质金属蛋白酶-9水平与患者的死亡率直接相关。因此，优势在于 心肌梗死后抑制基质金属蛋白酶-9的作用早已被认识到。然而，使用全局抑制基质金属蛋白酶-9的临床试验 由于缺乏基质金属蛋白酶抑制物的特异性和基质金属蛋白酶-9在几个关键因素中的重要性 流程。 我们最近发现了一种细胞外基质衍生的多肽(P1159)，它作为一种竞争性和特异性的基质金属蛋白酶-9底物。 在此，我们建议使用p1159来调节心肌梗死后天然底物的基质金属蛋白酶-9的切割。这种方法做到了 不抑制基质金属蛋白酶-9的活性，使其参与必要的过程；相反，它调节基质金属蛋白酶-9 蛋白质分解能力，减少促进炎症和抑制修复的内源底物的裂解。 合成肽p1159是由基质金属蛋白酶-9产生的自然形成的片段C-1158/59的模拟物 心肌梗死后胶原蛋白裂解。在人类中，心肌梗死后血浆内源性C-1158/59水平与较低的 左心室充盈压，表明C-1158/59具有治疗潜力。事实上，用外源激素治疗的小鼠 心肌梗死后心肌梗死后P1159表现出较少的左室扩张，减少炎症和纤维化，改善心功能。在……里面 在体外，我们发现整合素α4(ItGa4)是一种多肽受体。虽然我们知道外源性分娩是有益的， P1159如何调控心肌梗死后炎症和细胞外基质沉积尚未进行机械解剖。 因此，这一提议的中心假设是，p1159通过服务来钝化MI后的不利重塑 作为竞争性底物以减少促进炎症所必需的底物的基质金属蛋白酶-9的蛋白分解 和细胞外基质沉积。阐明p1159在心肌梗死后的作用模式和信号转导途径 ，我们将使用细胞特异性的Itga4转基因动物来确定p1159脾气的机制 心肌梗死后的炎症反应，调节心脏成纤维细胞信号，减少ECM的分泌； 促进巨噬细胞-成纤维细胞的串扰。

PROJECT SUMMARY Myocardial infarction (MI) leads to the generation of a scar that is mostly constituted by cardiac extracellular matrix (ECM). The balance between degradation and deposition of ECM is a strong predictor of clinical outcomes. ECM degradation occurs by matrix metalloproteinases (MMPs); and ECM deposition occurs by cardiac fibroblasts. Both ECM degradation and deposition promote adverse remodeling and progression to heart failure. Within the MMP family, MMP-9 has been reported as a prognostic indicator of cardiac dysfunction in myocardial infarction (MI) patients; as MMP-9 levels directly associate with patient mortality. Thus, the advantage of inhibiting MMP-9 after MI has been long recognized. However, clinical trials using global MMP-9 inhibition have mostly failed both due to lack of MMP inhibitor specificity and importance of MMP-9 in several essential processes. We recently identified an ECM-derived peptide (p1159) that acts as a competitive and specific MMP-9 substrate. Herein, we propose use of p1159 to modulate MMP-9 cleavage of native substrates post-MI. This approach does not inhibit MMP-9 activity, allowing it to participate in essential processes; instead, it modulates MMP-9 proteolytic capacity to reduce cleavage of endogenous substrates that promote inflammation and inhibit repair. The synthetic peptide p1159 is a mimetic of the naturally formed fragment C-1158/59 generated by MMP-9 cleavage of collagen post-MI. In humans, plasma levels of endogenous C-1158/59 post-MI correlate with lower left ventricle filling pressure, indicating a therapeutic potential of C-1158/59. Indeed, mice treated with exogenous p1159 post-MI display less LV dilation, reduced inflammation and fibrosis, and improved cardiac function. In vitro, we identified integrin α4 (Itga4) as a peptide receptor. While we know that exogenous delivery is beneficial, how p1159 regulates post-MI inflammation and ECM deposition has not been mechanistically dissected. Accordingly, the central hypothesis of this proposal is that p1159 blunts adverse remodeling after MI by serving as a competitive substrate to reduce MMP-9 proteolysis of substrates necessary for promotion of inflammation and ECM deposition. To elucidate the mode-of-action and signaling pathways mediated by p1159 in the post-MI setting, we will use cell-specific Itga4 transgenic animals to identify the mechanisms whereby p1159 tempers the post-MI inflammatory response, modulates cardiac fibroblast signaling to reduce ECM secretion; and promotes macrophage-fibroblast crosstalk.