Roten L, Nemoto S, Simsic J, Coker M L, Rao V, Baicu S, Defreyte G, Soloway P J, Zile M R, Spinale F G
Division of Cardiothoracic Surgery and Cardiology, Medical University of South Carolina and Roswell Park Cancer Institute, Buffalo, New York, USA.
J Mol Cell Cardiol. 2000 Jan;32(1):109-20. doi: 10.1006/jmcc.1999.1052.
Alterations in the expression and activity of the matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in tissue remodeling in a number of disease states. One of the better characterized TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP activational process. The goal of this study was to determine whether deletion of the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV myocardium, would produce time-dependent effects on LV geometry and function. Age-matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP-1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic studies at 1 and 4 months of age. LV catheterization studies were performed at 4 months and the LV harvested for histomorphometric studies. LV end-diastolic volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months in the TIMP-1 KO group; a significant increase compared to wild-type controls (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two-fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic pressure and ejection performance were unchanged in the two groups of mice. LV myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to controls, but myocardial fibrillar collagen content was reduced. Changes in LV geometry occurred in TIMP-1 deficient mice and these results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure.
基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）的表达和活性改变与多种疾病状态下的组织重塑有关。TIMP-1是特征较为明确的TIMPs之一，已被证明可与活性MMPs结合并调节MMP的激活过程。本研究的目的是确定小鼠TIMP-1基因缺失（这将导致左心室心肌中TIMP-1表达缺失）是否会对左心室几何形状和功能产生时间依赖性影响。对年龄匹配的TIMP-1基因缺陷的同窝小鼠（129Sv，TIMP-1基因敲除（TIMP-1 KO），n = 10）和野生型小鼠（n = 10）在1个月和4个月大时进行了比较超声心动图研究。在4个月时进行左心室插管研究，并采集左心室用于组织形态计量学研究。TIMP-1 KO组在4个月时左心室舒张末期容积和质量增加（分别增加18±4%和38±3%，P<0.05）；与野生型对照组相比有显著增加（P<0.05）。在4个月时，与野生型相比，TIMP-1 KO组的左心室和舒张末期壁应力增加了两倍多（P<0.05）。然而，两组小鼠的左心室收缩压和射血性能没有变化。与对照组相比，TIMP-1 KO小鼠的左心室心肌细胞横截面积没有变化，但心肌纤维胶原含量减少。TIMP-1缺陷小鼠出现了左心室几何形状的改变，这些结果表明组成型TIMP-1表达参与维持正常的左心室心肌结构。
