Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition
Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition
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DOI：
10.1152/ajpheart.00370.2004
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发表时间：
2005-01-01
影响因子：
4.8
通讯作者：
Spinale, FG
中科院分区：
文献类型：
--
作者：
Ikonomidis, JS;Hendrick, JW;Spinale, FG
基质金属蛋白酶（MMPs）和基质金属蛋白酶组织抑制剂（TIMPs）的改变与心肌梗死（MI）后左心室（LV）重构有关。然而，TIMPs在心肌梗死后重构过程中的直接机制作用尚未完全确定。本项目的目的是确定通过遗传和药理学方法联合改变内源性MMP抑制控制对小鼠心肌梗死后重塑的影响。本研究在野生型（WT）小鼠和TIMP-1基因缺陷小鼠[TIMP-1敲除（TIMP 1-KO）]中检查了PD-166793（30mg.kg（-1）.day（-1））MMP抑制（MMPi）对MI后LV几何形状和功能（电导容量法）的影响。在MI（冠状动脉结扎）后3天，将小鼠随机分为四组：WT-MI/MMPi（n = 10）、TIMP 1-KO-MI/MMPi（n = 10）、WT-MI（n = 22）和TIMP 1-KO-MI（n = 23）。MI后14天测定左室舒张末期容积（EDV）和射血分数。将经配对的WT（n = 20）和TIMP 1-KO（n = 28）小鼠作为参考对照。在对照条件下，WT和TIMP 1-KO小鼠的LVEDV相似（分别为36 +/- 2和40 +/- 2穆尔），但TIMP 1-KO-MI小鼠的LVEDV大于WT-MI小鼠（48 +/- 2 vs.61 +/- 5穆尔，P < 0.05）。在WT-MI/MMPi和TIMP 1-KO-MI/MMPi小鼠中，LVEDV从仅MI值降低（分别为42 +/-2和36 +/-2 μ l，P < 0.05），但在TIMP 1-KO小鼠中降低至最大程度（P < 0.05）。MI后两组的LV射血分数均降低，TIMP 1-KO-MI/MMPi小鼠的LV射血分数升高，但WT-MI/MMPi小鼠的LV射血分数未升高。这些独特的结果表明，心肌TIMP-1在MI后重塑中起着调节作用，并且TIMP-1基因缺失诱导的加速心肌重塑可以通过MMP抑制而被“拯救”。这些结果明确了局部内源性MMP活性控制在MI后调节LV结构和功能方面的重要性。
Alterations in matrix metalloproteinases ( MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 ( 30 mg.kg(-1).day(-1)) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/MMPi (n = 10), TIMP1-KO-MI/MMPi (n = 10), WT-MI (n = 22), and TIMP1-KO-MI (n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT (n = 20) and TIMP1-KO (n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 +/- 2 and 40 +/- 2 mul, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 +/- 2 vs. 61 +/- 5 mul, P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 +/- 2 and 36 +/- 2 mu l, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice (P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically "rescued" by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI.