Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor α can be modulated by anti-tumor necrosis factor α therapy
Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor α can be modulated by anti-tumor necrosis factor α therapy
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DOI：
10.1073/pnas.97.23.12746
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Feldman, AM
中科院分区：
文献类型：
--
作者：
Li, YY;Feng, YQ;Feldman, AM
由细胞外基质（ECM）重塑引起的心肌纤维化与衰竭心脏的功能障碍有关。基质金属蛋白酶（MMP）调节ECM重塑，并受到细胞因子的调节。心脏特异性过表达肿瘤坏死因子α（TNF-α）（TNF 1.6）的转基因小鼠发生心力衰竭。我们假设TNF-α和/或MMP活性的调节可能改变心肌ECM重塑过程和心力衰竭的发展。为了验证这一假设，我们利用TNF 1.6小鼠，通过羟脯氨酸定量、Sircol胶原测定、北方印迹分析和免疫组织化学研究可溶性和总胶原和胶原类型谱，并通过超声心动图研究心肌功能。在TNF 1.6小鼠中进行性心室肥大和扩张伴随着MMP-2和MMP-9活性的显著增加，胶原合成、沉积和变性的增加，以及未变性胶原的减少。在年轻的TNF 1.6小鼠中，ECM的这些变化与显著的舒张功能障碍相关，如经二尖瓣多普勒超声心动图E/A波比值显著降低所示。用表达可溶性TNF-α受体I型的腺病毒载体进行抗TNF-α治疗，可减弱MMP-2和MMP-9的活性，阻止胶原蛋白的进一步合成、沉积和变性，并保留年轻但非老年TNF-1.6小鼠的心肌舒张功能。结果表明，TNF-α和MMPs在心肌基质重塑和功能调节中起关键作用，并支持TNF-α和MMPs可能作为心力衰竭治疗的潜在治疗靶点的假设。
Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remodeling is implicated in the dysfunction of the failing heart. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that modulation of TNF-alpha and/or MMP activity might alter the myocardial ECM remodeling process and the development of heart failure. To test this hypothesis, we took advantage of the TNF1.6 mice and studied soluble and total collagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry and studied myocardial function by using echocardiography. Progressive ventricular hypertrophy and dilation in the TNF1.6 mice were accompanied by a significant increase in MMP-2 and MMP-9 activity, an increase in collagen synthesis, deposition, and denaturation, and a decrease in undenatured collagens. In young TNF1.6 mice, these changes in the ECM were associated with marked diastolic dysfunction as demonstrated by significantly reduced transmitral Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated both MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposition and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and support the hypothesis that both TNF-alpha and MMPs may serve as potential therapeutic targets in the treatment of heart failure.