Tissue injury results in profound alterations in the collagen network, associated with unfolding of the collagen triple helix, proteolytic degradation and generation of fragments. In the infarcted myocardium, changes in the collagen network are critically involved in the pathogenesis of left ventricular rupture, adverse remodeling and chronic dysfunction. We hypothesized that myocardial infarction is associated with temporally and spatially restricted patterns of collagen denaturation that may reflect distinct molecular mechanisms of collagen unfolding. We used a mouse model of non-reperfused myocardial infarction, and in vitro assays in fibroblast-populated collagen lattices. In healing infarcts, labeling with collagen hybridizing peptide (CHP) revealed two distinct patterns of collagen denaturation. During the inflammatory and proliferative phases of infarct healing, collagen denaturation was pericellular, localized in close proximity to macrophages and myofibroblasts. qPCR array analysis of genes associated with matrix remodeling showed that Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) is markedly upregulated in infarct macrophages and fibroblasts, suggesting its involvement in pericellular collagen denaturation. In vitro, MT1-MMP-mediated pericellular collagen denaturation is involved in cardiac fibroblast migration. The effects of MT1-MMP on collagen denaturation and fibroblast migration involve the catalytic site, and require hemopexin domain-mediated actions. In contrast, during the maturation phase of infarct healing, extensive collagen denaturation was noted in the hypocellular infarct, in the infarct border zone and in the mitral valve annulus, in the absence of MT1-MMP. In vitro, mechanical tension in attached collagen lattices was sufficient to induce peripheral collagen denaturation. Our study suggests that in healing infarcts, early pericellular collagen denaturation may be important for migration of macrophages and reparative myofibroblasts in the infarct. Extensive denaturation of collagen fibers is noted in mature scars, likely reflecting mechanical tension. Chronic collagen denaturation may increase susceptibility of the matrix to proteolysis, thus contributing to progressive cardiac dilation and post-infarction heart failure.

组织损伤导致胶原网络发生深刻变化，这与胶原三螺旋的展开、蛋白水解降解和碎片的产生有关。在梗塞心肌中，胶原网络的变化与左心室破裂、不良重构和慢性功能障碍的发病机制密切相关。我们假设心肌梗死与时间和空间受限的胶原蛋白变性模式有关，这可能反映了胶原蛋白展开的不同分子机制。我们使用了非再灌注心肌梗死的小鼠模型，并在成纤维细胞聚集的胶原蛋白晶格中进行了体外测定。在治愈梗塞时，用胶原蛋白杂交肽 (CHP) 标记揭示了两种不同的胶原蛋白变性模式。在梗塞愈合的炎症和增殖阶段，胶原蛋白变性发生在细胞周围，位于巨噬细胞和肌成纤维细胞附近。与基质重塑相关的基因的 qPCR 阵列分析表明，膜 1 型基质金属蛋白酶 (MT1-MMP) 在梗塞巨噬细胞和成纤维细胞中显着上调，表明其参与细胞周围胶原蛋白变性。在体外，MT1-MMP 介导的细胞周围胶原蛋白变性参与心脏成纤维细胞迁移。MT1-MMP 对胶原蛋白变性和成纤维细胞迁移的影响涉及催化位点，并且需要血红素结合蛋白结构域介导的作用。相反，在梗塞愈合的成熟阶段，在细胞不足的梗塞中观察到广泛的胶原变性，在没有 MT1-MMP 的情况下，在梗塞边界区和二尖瓣环中。在体外，附着的胶原蛋白晶格中的机械张力足以诱导外周胶原蛋白变性。我们的研究表明，在梗塞愈合过程中，早期细胞外周胶原蛋白变性可能对梗塞中巨噬细胞和修复性肌成纤维细胞的迁移很重要。在成熟的疤痕中注意到胶原纤维的广泛变性，这可能反映了机械张力。慢性胶原蛋白变性可能会增加基质对蛋白水解的敏感性，从而导致进行性心脏扩张和梗死后心力衰竭。我们的研究表明，在梗塞愈合过程中，早期细胞外周胶原蛋白变性可能对梗塞中巨噬细胞和修复性肌成纤维细胞的迁移很重要。在成熟的疤痕中注意到胶原纤维的广泛变性，这可能反映了机械张力。慢性胶原蛋白变性可能会增加基质对蛋白水解的敏感性，从而导致进行性心脏扩张和梗死后心力衰竭。我们的研究表明，在梗塞愈合过程中，早期细胞外周胶原蛋白变性可能对梗塞中巨噬细胞和修复性肌成纤维细胞的迁移很重要。在成熟的疤痕中注意到胶原纤维的广泛变性，这可能反映了机械张力。慢性胶原蛋白变性可能会增加基质对蛋白水解的敏感性，从而导致进行性心脏扩张和梗死后心力衰竭。