From the Department of Physiology (A.T., P.Z., X.W., G.O., Z.K.), Department of Medicine/Division of Cardiology (V.B.P., G.O.), and Cardiovascular Research Center, Mazankowski Alberta Heart Institute (A.T., P.Z., V.B.P., X.W., G.O., Z.K.), University of Alberta, Edmonton, Canada.
Hypertension. 2017 Jun;69(6):1092-1103. doi: 10.1161/HYPERTENSIONAHA.117.09045. Epub 2017 Apr 3.
Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies.
心肌纤维化是细胞外基质纤维胶原的过度积累。纤维化是各种心肌病的一个关键特征，会损害心脏的收缩和舒张功能。TIMP1（金属蛋白酶组织抑制剂 1）在心肌纤维化中始终上调，并被用作纤维化的标志物。然而，TIMP1 是否通过抑制基质金属蛋白酶降解细胞外基质或通过基质金属蛋白酶非依赖性途径来促进组织纤维化，仍有待确定。我们使用 TIMP1 缺陷小鼠和两种心肌纤维化的体内模型（血管紧张素 II 输注和心脏压力超负荷）、成年心脏成纤维细胞的体外分析以及扩张型心肌病（DCM）患者的纤维化心肌，研究了 TIMP1 在心肌纤维化中的功能。TIMP1 缺陷显著减少了两种心肌病的体内模型中的心肌纤维化。我们确定了 TIMP1 作用的一种新机制，即独立于其基质金属蛋白酶抑制功能，它介导 TIMP1 与心脏成纤维细胞上的 CD63（TIMP1 的细胞表面受体）和整合素β1 之间的关联，启动 Smad2/3 和 β-catenin 的激活和核易位，导致新的胶原合成。这种机制在体内、在培养的心脏成纤维细胞中和在人类纤维化心肌中都得到了一致的观察。此外，在长期压力超负荷后，TIMP1 缺陷持续减少心肌纤维化并改善舒张功能障碍。这项研究定义了 TIMP1 在促进心肌纤维化中的一种新的基质金属蛋白酶非依赖性功能。因此，靶向 TIMP1 可能被证明是开发抗纤维化疗法的一种有价值的方法。
