Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure - Relation to ventricular and myocyte function
Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure - Relation to ventricular and myocyte function
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DOI：
10.1161/01.res.82.4.482
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发表时间：
1998-03-09
影响因子：
20.1
通讯作者：
Hebbar, L
中科院分区：
文献类型：
--
作者：
Spinale, FG;Coker, ML;Hebbar, L
充血性心力衰竭（CHF）的发生与左心室（LV）扩张和心肌重塑有关。然而，随着CHF的进展，导致这种重塑过程的基本机制仍不清楚。基质金属蛋白酶（matrix metalloproteinases，MMPs）在许多病理过程中的组织重塑中起重要作用。本项目验证了CHF进展过程中LV扩张和重塑与MMP表达和酶谱活性、LV和肌细胞功能、胶原含量以及MMP表达和酶谱活性的早期变化相关的假设;在猪起搏诱导的室上性心动过速（SVT）引起的CHF进展过程中连续测量，SVT 7天后，左心室舒张末期尺寸和肌细胞长度均较对照值增加15%，左心室短缩率下降20%。在心肌细胞水平，SVT 7天后缩短百分比下降了16%，而稳态缩短速度没有变化。持续时间较长的室上性心动过速导致进行性左心室扩张、左心室泵衰竭和心肌细胞收缩功能障碍。具体而言，21天的SVT导致LV尺寸增加>50%，LV缩短分数下降56%，以及肌细胞缩短速度下降33%。SVT 21天的LV和肌细胞功能下降伴有CHF的体征和症状。因此，室上性心动过速导致LV几何形状和功能的时间依赖性变化以及随后的CHF发展。室上性心动过速7天后，左心室心肌胶原含量和汇合度下降>25%，同时左心室心肌基质金属蛋白酶对底物明胶的酶谱活性增加80%。SVT 14天后，左室心肌总胶原含量减少24%，左室心肌MMP酶谱活性增加>100%。SVT 7天后，间质胶原酶（MMP-1）、基质溶解素（MMP-3）和72-kD明胶酶（MMP-2）增加约2倍。随着SVT持续时间的延长，LV MMP酶谱活性和丰度仍升高。本研究的结果表明，在这个CF模型中，LV心肌MMP酶谱活性和蛋白水平的早期变化发生在LV扩张和功能障碍的开始和进展。这些结果表明，在这种发展中的CHF模型中发生的LV重构的启动的早期贡献机制是LV心肌MMPs的表达增强和潜在活性增加。
The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity, LV and myocyte function, collagen content, and MMP expression and zymographic activity; were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs, After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimension, a 56% fall in LV fractional; shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by >100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by approximate to 2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CF, early changes in LV myocardial MMP zymographic activity and protein levels occurred with the initiation and progression of LV dilation and dysfunction. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV myocardial MMPs.