TNF-like weak inducer of apoptosis aggravates left ventricular dysfunction after myocardial infarction in mice.
TNF-like weak inducer of apoptosis aggravates left ventricular dysfunction after myocardial infarction in mice.
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DOI：
10.1155/2014/131950
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发表时间：
2014
影响因子：
4.6
通讯作者：
Chorianopoulos E
中科院分区：
文献类型：
--
作者：
Jarr KU;Eschricht S;Burkly LC;Preusch M;Katus HA;Frey N;Chorianopoulos E
背景资料。最近发现，肿瘤坏死因子样的弱凋亡诱导因子(TWEEP)可能与心脏的不良重构有关。然而，TWINE本身及其受体Fn14在这种情况下的确切作用尚不清楚。本研究的目的。目的：分析sTWEAK对实验性心肌梗死小鼠心肌功能及基因表达的影响。结果。TWEE直接抑制心肌细胞PGC-1α和氧化磷酸化基因的表达。心肌梗死后全身应用sTWEAK导致左心功能下降和死亡率增加，而间质纤维化或梗塞面积没有改变。分子分析显示，PI3K/Akt和ERK1/2途径的磷酸化水平降低与PGC-1α和PPARα表达降低有关。同样，OXPHOS基因如atp50、cycs、cox5b和ndufb5的表达也降低。与WT小鼠(Fn14+/+)相比，Fn14−/−小鼠心肌梗死后左心功能和pGC-1α水平显著改善。最后，用抗TWAKE抗体抑制固有TWAGE可改善左心功能，提高存活率。结论。在小鼠心肌梗死后，TWEAM对心肌细胞产生不适应作用，很可能是通过直接作用于心肌细胞。对潜在机制的分析表明，TWINE通过抑制PGC-1α而降低了对心脏工作负荷增加的代谢适应。
Background. TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. Results. TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS) in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14 −/− mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14 +/+). Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. Conclusions. TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.