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(Circulation. 2003;108:1002.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype

Ziad I. Dibbs, MD^*; Abhinav Diwan, MBBS^*; Shintaro Nemoto, MD, PhD; Gilberto DeFreitas, BS; Maha Abdellatif, MD, PhD; Blase A. Carabello, MD; Francis G. Spinale, MD, PhD; Giora Feuerstein, PhD; Natarajan Sivasubramanian, PhD; Douglas L. Mann, MD

From the Winters Center for Heart Failure Research (Z.I.D., A.D., N.S., D.L.M.), Baylor College of Medicine, and the Medical Service Care Line (S.N., G.D., B.A.C.), Houston Veterans Affairs Medical Center, Houston, Tex; the Department of Cell Biology and Molecular Medicine (M.A.), University of Medicine and Dentistry of New Jersey, Newark; Merck Research Laboratories (G.F.), West Point, Pa; and the Department of Surgery (F.G.S.), Cardiothoracic Research, Medical University of South Carolina, Charleston.

Correspondence to Douglas L Mann, MD, Winters Center for Heart Failure Research, F770, 6565 Fannin, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu

Received January 23, 2003; revision received May 6, 2003; accepted May 13, 2003.

Background— Tumor necrosis factor (TNF) is initially synthesized as a 26-kDa transmembrane protein that is enzymatically cleaved by TNF- 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.

Key Words: hypertrophy • growth substances • genes • tumor necrosis factor

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