Mice with Tissue Inhibitor of Metalloproteinases 4 (Timp4) Deletion Succumb to Induced Myocardial Infarction but Not to Cardiac Pressure Overload
Mice with Tissue Inhibitor of Metalloproteinases 4 (Timp4) Deletion Succumb to Induced Myocardial Infarction but Not to Cardiac Pressure Overload
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DOI：
10.1074/jbc.m110.136820
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Khokha, Rama
中科院分区：
文献类型：
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作者：
Koskivirta, Ilpo;Kassiri, Zamaneh;Khokha, Rama
金属蛋白酶组织抑制剂4（TIMP 4）在心脏组织中高表达，在心血管疾病中表达异常。它通过抑制基质金属蛋白酶（MMPs）来控制细胞外基质重塑，并参与细胞增殖、凋亡和血管生成等过程。产生Timp 4缺陷型小鼠（Timp 4（-/-））以评估TIMP 4在正常发育和心脏病模型中的功能。我们通过同源重组删除了Timp 4基因的外显子1-3。Timp 4（-/-）小鼠出生时健康，发育正常，并产生正常大小和性别分布的窝仔。这些小鼠在心脏中没有表现出Timp 1、Timp 2或Timp 3的过表达的补偿。主动脉结扎导致心脏压力超负荷后，Timp 4（-/-）小鼠的存活率、心脏组织学和心脏功能与对照组相当。在这种情况下，Timp 4缺陷通过增加心脏Timp 2表达来补偿。引人注目的是，诱导心肌梗死（MI）导致Timp 4（-/-）小鼠死亡率显著增加，主要是由于左心室破裂。Timp 4（-/-）小鼠的MI后死亡率通过施用合成MMP抑制剂而降低。此外，结合Mmp 2的遗传缺失也挽救了Timp 4（-/-）小鼠的较高的MI后死亡率。最后，Timp 4（-/-）小鼠在20个月大时心脏功能下降。TIMP 4对于小鼠发育不是必需的，尽管其损失随着年龄的增长适度地损害心脏功能。TIMP 4（-/-）小鼠对MI更敏感，但对压力超负荷不敏感，并且TIMP 4在心肌梗死后以其作为金属蛋白酶抑制剂的能力起作用。
Tissue inhibitor of metalloproteinases 4 (TIMP4) is expressed highly in heart and found dysregulated in human cardiovascular diseases. It controls extracellular matrix remodeling by inhibiting matrix metalloproteinases (MMPs) and is implicated in processes including cell proliferation, apoptosis, and angiogenesis. Timp4-deficient mice (Timp4(-/-)) were generated to assess TIMP4 function in normal development and in models of heart disease. We deleted exons 1-3 of the Timp4 gene by homologous recombination. Timp4(-/-) mice are born healthy, develop normally, and produce litters of normal size and gender distribution. These mice show no compensation by overexpression of Timp1, Timp2, or Timp3 in the heart. Following cardiac pressure overload by aortic banding, Timp4(-/-) mice have comparable survival rate, cardiac histology, and cardiac function to controls. In this case, Timp4 deficiency is compensated by increased cardiac Timp2 expression. Strikingly, the induction of myocardial infarction (MI) leads to significantly increased mortality in Timp4(-/-) mice primarily due to left ventricular rupture. The post-MI mortality of Timp4(-/-) mice is reduced by administration of a synthetic MMP inhibitor. Furthermore, combining the genetic deletion of Mmp2 also rescues the higher post-MI mortality of Timp4(-/-) mice. Finally, Timp4(-/-) mice suffer reduced cardiac function at 20 months of age. Timp4 is not essential for murine development, although its loss moderately compromises cardiac function with aging. Timp4(-/-) mice are more susceptible to MI but not to pressure overload, and TIMP4 functions in its capacity as a metalloproteinase inhibitor after myocardial infarction.