Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice
Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice
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DOI：
10.1016/s0002-9440(10)62228-6
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发表时间：
2005-01-01
影响因子：
6
通讯作者：
Moons, L
中科院分区：
文献类型：
--
作者：
Heymans, S;Lupu, F;Moons, L
左心室（LV）肥大是心脏对压力负荷增加的自然反应，但伴随的纤维化和扩张可能导致不可逆的危及生命的心力衰竭。基质金属蛋白酶（MMP）已被调用在各种心脏疾病，然而，纤溶酶原激活剂（PA）和MMP系统的压力超负荷诱导的左心室肥大和心力衰竭的作用的直接遗传证据是缺乏的。因此，在缺乏组织型PA（t-PA（-/-））、尿激酶型PA（u-PA（-/-））或明胶酶-B（MMP-9（-/-））的小鼠中，以及在PA抑制剂派-1或MMP抑制剂TIMP-1的腺病毒基因转移后的野生型（WT）小鼠中，分析了横向主动脉束带（TAB）的后果。TAB使所有基因型的左室压力升高。在WT和t-PA（-/-）小鼠中，心肌细胞肥大与7周后的心肌纤维化、LV扩张和功能障碍以及泵衰竭相关。相反，在派-1-和TIMP-1-基因转移后，u-PA（-/-）小鼠或WT小鼠中，心肌细胞肥大是中度的，仅与心脏纤维化和LV扩张最低程度相关，导致泵功能更好地保留。MMP-9的缺乏具有中间效应。这些结果表明，使用u-PA-或MMP-抑制剂可能会保护心脏泵功能在LV压力超负荷。
Left ventricular (LV) hypertrophy is a natural response of the heart to increased pressure loading, but accompanying fibrosis and dilatation may result in irreversible life-threatening heart failure. Matrix metalloproteinases (MMPs) have been invoked in various cardiac diseases, however, direct genetic evidence for a role of the plasminogen activator (PA) and MMP systems in pressure overload-induced LV hypertrophy and in heart failure is lacking. Therefore, the consequences of transverse aortic banding (TAB) were analyzed in mice lacking tissue-type PA (t-PA(-/-)), urokinase-type PA (u-PA(-/-)), or gelatinase-B (MMP-9(-/-)), and in wild-type (WT) mice after adenoviral gene transfer of the PA-inhibitor PAI-1 or the MMP-inhibitor TIMP-1. TAB elevated LV pressure comparably in all genotypes. In WT and t-PA(-/-) mice, cardiomyocyte hypertrophy was associated with myocardial fibrosis, LV dilatation and dysfunction, and pump failure after 7 weeks. in contrast, in u-PA(-/-) mice or in WT mice after PAI-1- and TIMP-1-gene transfer, cardiomyocyte hypertrophy was moderate and only minimally associated with cardiac fibrosis and LV dilatation, resulting in better preservation of pump function. Deficiency of MMP-9 had an intermediate effect. These findings suggest that the use of u-PA- or MMP-inhibitors might preserve cardiac pump function in LV pressure overloading.