Tumor necrosis factor receptor-associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart.
Tumor necrosis factor receptor-associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart.
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DOI：
10.1161/circheartfailure.112.000080
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Mann DL
中科院分区：
文献类型：
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作者：
Divakaran VG;Evans S;Topkara VK;Diwan A;Burchfield J;Gao F;Dong J;Tzeng HP;Sivasubramanian N;Barger PM;Mann DL
肿瘤坏死因子(TRAF2)超家族配体通过一种称为肿瘤坏死因子受体相关因子2(TRAF2)的常见支架蛋白来激发扩张的心脏表型信号；然而，关于TRAF2在成年哺乳动物心脏中的信号转导几乎一无所知。我们建立了TRAF2心脏限制性过表达小鼠的多个创始细胞系，并鉴定了TRAF2高表达小鼠的表型(MHC-TRAF2HC)。MHC-TRAF2HC转基因小鼠的心肌肥厚、左室扩张和不良左室重构均呈时间依赖性增加，LV+dp/dt和−dp/dt显著降低(P<；0.05)。在LV重构的早期，总基质金属蛋白酶(MMPs)活性显着升高，而心肌纤维总胶原含量则下降。随着MHC-TRAF2HC小鼠年龄的增长，总的基质金属蛋白酶活性显著降低，同时总纤维胶原含量增加，心肌组织金属蛋白酶抑制物-1水平增加。MHCs TRAF2HC小鼠4~12周时核因子-JNKB活性显著升高，4周时κ活性显著升高。转录图谱显示，在MHC-TRAF2HC心脏中显著上调的肥厚/扩张型心肌病相关基因中，有95%在其启动子中含有κB元件。这些结果首次表明，TRAF2的靶向过表达足以介导心脏的不利心脏重构。
Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart. We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters. These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.