Differential expression of MMPs and TIMPs in moderate and severe heart failure in a transgenic model
Differential expression of MMPs and TIMPs in moderate and severe heart failure in a transgenic model
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DOI：
10.1016/j.cardfail.2006.01.009
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发表时间：
2006-05-01
影响因子：
6
通讯作者：
McTiernan, CF
中科院分区：
文献类型：
--
作者：
Mori, S;Gibson, G;McTiernan, CF
背景资料：基质金属蛋白酶（MMPs）及其内源性抑制剂（TIMPs）的表达改变伴随着心力衰竭（HF）的发展。然而，MMP和TIMP蛋白水平或活性的变化，在从代偿失代偿failure的进展仍然不完全examined.Methods和结果：转基因小鼠（Tg）与心脏特异性过度表达肿瘤坏死因子-α（TNF1.6）开发一个性别相关的，进行性的心脏扩张和HF。使用超声心动图测量对4至50周龄的雄性（M）和雌性（F）Tg和野生型（WT）小鼠的HF严重程度进行分类。在相似的年龄测量心脏TIMPs-1、TIMPs-2和MMP-3（酶联免疫吸附试验）以及潜在的（APMA激活的）MMP-9活性。原位酶谱法评估组织明胶酶活性。在年轻的M Tg小鼠（18周）和年长的F Tg小鼠（> 34周）中，收缩功能、心室尺寸和胸腔积液的存在确定了重度HF。与年龄、性别或HF严重程度无关，Tg小鼠表达显著更多的TIMP-1（Tg 119-193 pg/ mg vs. WT 13-24 pg/mg，P < .001）和潜在的MMP-9活性（Tg 0.41-0.58 ng/mg vs. WT 0.015-0.028 ng/mg，P < .002）。M Tg表达升高的MMP-3（4周，0.16 +/- 0.1 ng/mg蛋白质vs. WT 0.04 +/- 0.01 ng/mg，P < .003），其随着年龄和HF严重程度而增加（18周，0.51 +/- 0.3 ng/mg P < .01）。F Tg显示MMP-3在4周时没有增加，但随着年龄和HF严重程度而进行性增加（18周0.09 +/- 0.04 ng/mg，P <0.02相对于Tg M或WT; 34周0.13 +/- 0.02 ng/mg，P <0.001相对于WT）。为了验证这一假设，增加MMP-3可能差异激活MMP-9在M Tg，在原位酶谱进行，并揭示了一个显着增加明胶酶活性在M Tg小鼠相对于WT和F Tg。结论：MMP-3可能调节激活MMP-9/明胶酶，心脏重塑的进展，和发展失代偿性心力衰竭。
Background: Altered expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) accompanies the development of heart failure (HF). However, changes in MMP and TIMP protein levels or activity during the progression from compensated to decompensated failure remains incompletely examined.Methods and Results: Transgenic mice (Tg) with cardiac-specific overexpression of tumor necrosis factor-alpha (TNF1.6) develop a sex-related, progressive cardiac dilation and HF. Echocardiographic measures were used to categorize HF severity in male (M) and female (F) Tg and wild-type (WT) mice between 4 and 50 weeks of age. Cardiac TIMPs-1 TIMPs-2, and MMP-3 (enzyme-linked immunosorbent assay), and potential (APMA-activated) MMP-9 activity were measured at similar ages. In situ zymography assessed tissue gelatinase activity. Systolic function, ventricular dimensions, and presence of pleural effusions identified severe HF in younger M Tg mice (by 18 weeks) and older F Tg (> 34 weeks). Regardless of age, sex, or HF severity, Tg mice expressed significantly more TIMP-1 (Tg 119-193 pg/ mg vs. WT 13-24 pg/mg, P < .001) and potential MMP-9 activity (Tg 0.41-0.58 ng/mg vs. WT 0.015-0.028 ng/mg, P < .002). M Tg expressed elevated MMP-3 (4 weeks, 0.16 +/- 0.1 ng/mg protein vs. WT 0.04 +/- 0.01 ng/mg, P < .003), which increased with age and HF severity (18 weeks, 0.51 +/- 0.3 ng/mg P < .01). F Tg showed no increase in MMP-3 at 4 weeks but a progressive increase with age and HF severity (18 weeks 0.09 +/- 0.04 ng/mg, P < .02 vs. Tg M or WT; 34 weeks 0.13 +/- 0.02 ng/mg, P < .001 vs. WT). To test the hypothesis that increased MMP-3 may differentially activate MMP-9 in M Tg, in situ zymography was performed and revealed a significant increase in gelatinase activity in M Tg mice relative to both WT and F Tg.Conclusion: MMP-3 may regulate activation of MMP-9/gelatinasc, the progression of cardiac remodeling, and development of decompensated heart failure.