Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype
Targeted overexpression of transmembrane tumor necrosis factor provokes a concentric cardiac hypertrophic phenotype
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DOI：
10.1161/01.cir.0000085203.46621.f4
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发表时间：
2003-08-26
期刊：
影响因子：
37.8
通讯作者：
Mann, DL
中科院分区：
文献类型：
--
作者：
Dibbs, ZI;Diwan, A;Mann, DL
背景-肿瘤坏死因子（TNF）最初合成为26-kDa的跨膜蛋白，其被TNF-α转化酶（TACE）酶促裂解以产生17-kDa形式的“分泌型”TNF。而分泌的TNF在心脏中的影响已被广泛的特点，跨膜TNF在hearts.Methods和结果的影响是未知的-我们产生的转基因小鼠与心脏限制性过表达的noncleavable，跨膜形式的TNF线。接下来，我们用TACE抑制剂（DPC-IDR 1）处理先前产生的具有心脏限制性表达可切割TNF的转基因小鼠品系（称为MHCsTNF小鼠），以确定TACE抑制是否会阻止在该转基因小鼠品系中发生的从向心性肥大向左心室（LV）扩张的转变。两个创始人线没有一个可证明的表型（M-41和M-45），而第三个线开发了同心肥大的心脏表型（M-48）。在6周龄的M-48线的表征表明，这条线开发同心肥大，增加肌细胞横截面积和胎儿基因程序的重新表达。4周的TACE抑制消除了MHCsTNF小鼠的LV扩张，并导致LV壁厚度增加和肌细胞横截面积增加，从而模拟了在具有不可裂解的跨膜TNF的小鼠中观察到的效果。在具有靶向的、心脏限制性TNF过表达的小鼠中，TNF的释放（即分泌）导致扩张型心肌病表型。
Background - Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF-alpha converting enzyme (TACE) to generate a 17-kDa form of "secreted" TNF. Whereas the effects of secreted TNF in the heart have been characterized extensively, the effects of transmembrane TNF in the heart are unknown.Methods and Results - We generated lines of transgenic mice with cardiac-restricted overexpression of a noncleavable, transmembrane form of TNF. We next treated a previously generated transgenic line of mice with cardiac-restricted expression of cleavable TNF ( referred to as MHCsTNF mice) with a TACE inhibitor (DPC-IDR1) to determine whether TACE inhibition would prevent the transition from concentric hypertrophy to left ventricular (LV) dilation that occurs in this line of transgenic mice. Two of the founder lines did not have a demonstrable phenotype (M-41 and M-45), whereas a third line developed a concentric hypertrophic cardiac phenotype (M-48). Characterization of the M-48 line at 6 weeks of age showed that this line developed concentric hypertrophy, with an increase in myocyte cross-sectional area and reexpression of the fetal gene program. Four weeks of TACE inhibition abrogated the LV dilation in the MHCsTNF mice and resulted in an increase in LV wall thickness and increased myocyte cross-sectional area, thus mimicking the effects observed in the mice with noncleavable, transmembrane TNF.Conclusions - These studies show that transmembrane TNF is biologically active and provokes a concentric hypertrophic cardiac phenotype, thus suggesting that posttranslational processing (ie, secretion) of TNF is responsible for the dilated cardiomyopathic phenotype in mice with targeted, cardiac-restricted overexpression of TNF.