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(Circulation. 2004;109:262-268.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Targeted Overexpression of Noncleavable and Secreted Forms of Tumor Necrosis Factor Provokes Disparate Cardiac Phenotypes

Abhinav Diwan, MD; Ziad Dibbs, MD; Shintaro Nemoto, MD, PhD; Gilberto DeFreitas, BS; Blase A. Carabello, MD; Natarajan Sivasubramanian, PhD; Eric M. Wilson, BS; Francis G. Spinale, MD, PhD; Douglas L. Mann, MD

From the Winters Center for Heart Failure Research (A.D., Z.D., N.S., D.L.M.), Medical Service Care Line (S.N., G.D., B.A.C.), Houston VAMC, Baylor College of Medicine and the Methodist Hospital, Houston, Tex; and Department of Surgery (E.M.W., F.G.S.), Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.

Correspondence to Douglas L. Mann, MD, Winters Center for Heart Failure Research, MS 524, 6565 Fannin, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu

Received July 21, 2003; revision received September 11, 2003; accepted September 22, 2003.

Background— Recent studies suggest that posttranslation processing or "shedding" (ie, secretion) of tumor necrosis factor (TNF) by tumor necrosis factor- converting enzyme (TACE) may contribute to the left ventricular (LV) remodeling that occurs in the failing human heart.

Methods and Results— To address the functional significance of TNF shedding, we generated lines of transgenic mice with targeted overexpression of secreted wild-type (MHCsTNF₂) TNF and overexpression of a mutated noncleavable transmembrane form of TNF (MHCmTNF). Both lines of mice had overlapping levels of myocardial TNF protein; however, the phenotypes of the MHCsTNF2 and MHCmTNF mice were strikingly disparate. Whereas the MHCmTNF mice developed a concentric LV hypertrophy phenotype, the MHCsTNF₂ mice developed a dilated LV phenotype. The fibrillar collagen weave in MHCmTNF mice with concentric hypertrophy was characterized by thick collagen fibrils and increased collagen content, whereas the fibrillar collagen weave in the MHCsTNF₂ mice with LV dilation was characterized by a diminished collagen content. Inhibition of matrix metalloproteinases with a broad-based matrix metalloproteinase inhibitor prevented LV dilation in the MHCsTNF₂ mice.

Conclusions— These findings suggest that posttranslational processing of TNF, as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression.

Key Words: hypertrophy • remodeling • metalloproteinases

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