Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction
Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction
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DOI：
10.1161/01.cir.0000147233.10318.23
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发表时间：
2004-11-16
期刊：
影响因子：
37.8
通讯作者：
Liu, PP
中科院分区：
文献类型：
--
作者：
Sun, M;Dawood, F;Liu, PP
背景-我们研究了肿瘤坏死因子-α在肿瘤细胞中的潜在作用方法和结果-将动物随机分为左前降支结扎组或假手术组，并在第3、7、10、12、14、16、18、19 14和28。我们监测心脏破裂率、心功能、炎症反应、胶原降解和净胶原形成。我们发现以下内容：（1）MI后1周内，WT组53.3%（n = 120）死于心脏破裂，而TNF-/-组仅2.5%（n = 80），（2）第3天WT组梗死区炎性细胞浸润和细胞因子表达明显高于TNF-/-组;（3）WT组心肌基质金属蛋白酶-9和-2活性在第3天显著高于TNF-/-组;（4）与假手术组比较，左室发展压力（74%）和+/-dP/dt（max）显著降低（68.3%/ 65.3%），但+/-dP/dt（max）降低不太显著TNF-/-小鼠为25.8%/ 28.8%;（5）第3天和第7天，WT小鼠的心脏胶原体积分数低于TNF-/-小鼠，但第28天高于TNF-/-小鼠;和（6）与WT小鼠相比，TNF-/-小鼠在第28天出现心肌细胞凋亡减少。结论-梗死心肌中局部TNF-α升高通过诱导旺盛的局部炎症反应、基质和胶原降解，基质金属蛋白酶活性增加和细胞凋亡。
Background - We investigated the potential contributions of tumor necrosis factor-alpha (TNF-alpha) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF-/-) mice compared with C57/BL wild-type (WT) mice.Methods and Results - Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (n = 120) of WT mice died of cardiac rupture, in contrast to 2.5% (n = 80) of TNF-/- mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF-/- mice on day 3; (3) matrix metalloproteinase-9 and - 2 activity in the infarcted myocardium was significantly higher in WT than in TNF-/- mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and +/-dP/dt(max) (68.3%/ 65.3%) in WT mice but a less significant decrease in +/-dP/dt(max) (25.8%/ 28.8%) in TNF-/- mice; ( 5) cardiac collagen volume fraction was lower in WT than in TNF-/- mice on days 3 and 7 but higher on day 28 compared with TNF-/- mice; and ( 6) a reduction in myocyte apoptosis in TNF-/- mice occurred on day 28 compared with WT mice.Conclusions - Elevated local TNF-alpha in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.