Dibbs Ziad I, Diwan Abhinav, Nemoto Shintaro, DeFreitas Gilberto, Abdellatif Maha, Carabello Blase A, Spinale Francis G, Feuerstein Giora, Sivasubramanian Natarajan, Mann Douglas L
Winters Center for Heart Failure Research, Houston, TX 77030, USA.
Circulation. 2003 Aug 26;108(8):1002-8. doi: 10.1161/01.CIR.0000085203.46621.F4. Epub 2003 Aug 11.
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.
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.
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.
肿瘤坏死因子（TNF）最初作为一种26 kDa的跨膜蛋白合成，该蛋白被TNF-α转换酶（TACE）酶切，生成17 kDa形式的“分泌型”TNF。尽管分泌型TNF在心脏中的作用已得到广泛研究，但其跨膜形式在心脏中的作用尚不清楚。
我们构建了心脏特异性过表达不可切割跨膜形式TNF的转基因小鼠品系。接下来，我们用TACE抑制剂（DPC-IDR1）处理先前构建的心脏特异性表达可切割TNF的转基因小鼠品系（称为MHCsTNF小鼠），以确定TACE抑制是否能阻止该品系转基因小鼠从向心性肥厚转变为左心室（LV）扩张。两个奠基品系没有明显的表型（M-41和M-45），而第三个品系出现了向心性肥厚的心脏表型（M-48）。对6周龄的M-48品系进行表征发现，该品系出现了向心性肥厚，心肌细胞横截面积增加，胎儿基因程序重新表达。四周的TACE抑制消除了MHCsTNF小鼠的LV扩张，导致LV壁厚度增加和心肌细胞横截面积增大，从而模拟了在不可切割跨膜TNF小鼠中观察到的效应。
这些研究表明，跨膜TNF具有生物活性，并引发向心性肥厚的心脏表型，这表明TNF的翻译后加工（即分泌）是导致TNF靶向性心脏特异性过表达小鼠扩张型心肌病表型的原因。
