Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats
Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats
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DOI：
10.1016/s0735-1097(02)01756-4
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发表时间：
2002-04-17
影响因子：
24
通讯作者：
Sasayama, S
中科院分区：
文献类型：
--
作者：
Iwanaga, Y;Aoyama, T;Sasayama, S
目的：我们试图阐明在左心室（LV）重构过程中，基质金属蛋白酶（MMPs）的局部活化是如何与内源性基质金属蛋白酶组织抑制剂（TIMPs）的活化相平衡的。
背景：尽管已知在左心室重构过程中细胞外基质（ECM）必然会发生改变，但其局部调节机制尚未完全阐明。
方法：在患有高血压的 Dahl盐敏感大鼠中，11周时出现向心性代偿性左心室肥厚（LVH）阶段，随后在17周时出现明显的充血性心力衰竭（CHF）阶段，伴有左心室扩大和功能障碍。我们测定了左心室心肌TIMP - 2和 - 4以及MMP - 2的蛋白质和信使核糖核酸（mRNA）水平，以及它们相应的活性。
结果：在左心室肥厚阶段未发现变化。然而，在向左心室心力衰竭转变过程中，TIMP - 2和 - 4的活性、蛋白质及mRNA水平均急剧升高。同时，通过明胶酶谱法以及抗体捕获试验测定的MMP - 2的mRNA、蛋白质水平及活性在向左心室心力衰竭转变过程中显著增加。体内净MMP活性与左心室直径增加（r = 0.703）以及收缩期壁应力增加（r = 0.858）密切相关。
结论：TIMP和MMP - 2在肥厚本身期间均保持无活性；它们在向左心室心力衰竭转变过程中被激活。此时，MMP - 2的活化超过了TIMP的活化，可能导致细胞外基质分解以及左心室扩大的进展。（《美国心脏病学会杂志》2002年；39卷：1384 - 91页）（©2002美国心脏病学会基金会）
OBJECTIVES We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling.BACKGROUND Although it is known that the extracellular matrix (ECM) must be altered during I,V remodeling, its local regulation has not been fully elucidated.METHODS In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left, ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities.RESULTS No changes were found at the LVH stage, However, during the transition to Cl IF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased, At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.703) and to systolic wall stress (r = 0.858) in vivo.CONCLUSIONS Both TIMPs and MMP-2 remained inactive during hypertrophy, per se: they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of I,V enlargement. (J Am Coll Cardiol 2002;39:1384-91) (C) 2002 by the American College of Cardiology Foundation.