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(Circulation. 2009;119:2058-2068.)
© 2009 American Heart Association, Inc.

Heart Failure

A Novel Role for Tumor Necrosis Factor–Like Weak Inducer of Apoptosis (TWEAK) in the Development of Cardiac Dysfunction and Failure

Mohit Jain, MD, PhD; Aniela Jakubowski, MS; Lei Cui, MD; Jianru Shi, PhD; Lihe Su, PhD; Michael Bauer, MD; Jian Guan, MD; Chee Chew Lim, PhD; Yoshiro Naito, MD, PhD; Jeffrey S. Thompson, BS; Flora Sam, MD; Christine Ambrose, PhD; Michael Parr, PhD; Thomas Crowell, BS; John M. Lincecum, PhD; Monica Z. Wang, BS; Yen-Ming Hsu, PhD; Timothy S. Zheng, PhD; Jennifer S. Michaelson, PhD; Ronglih Liao, PhD; Linda C. Burkly, PhD

From the Division of Cardiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.J., L.C., J.S., M.B., J.G., Y.N., R.L.); Biogen Idec, Inc, Cambridge, Mass (A.J., L.S., J.S.T., C.A., M.P., T.C., J.M.L., M.Z.W., Y.S., T.S.Z., J.S.M., L.C.B.); and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass (J.G., F.S.). L.C. and T.C. are currently at Novartis, Cambridge, Mass; C.C.L. is currently at the Department of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tenn; Y.N. is currently at Hyogo College of Medicine, Japan; M.P. is currently at Drug Development Inc, Vancouver, British Columbia; J.M.L. and M.Z.W. are currently at ALS Therapy Development Institute, Cambridge, Mass.

Correspondence to Ronglih Liao, PhD, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, 77 Ave Louis Pasteur, NRB 431, Boston, MA 02115 (e-mail rliao{at}rics.bwh.harvard.edu) and Linda Burkly, PhD, Biogen Idec, Inc, 12 Cambridge Center, Cambridge, MA 02142 (e-mail linda.burkly@biogenidec.com).

Received November 20, 2008; accepted February 9, 2009.

Background— Tumor necrosis factor–like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, is a multifunctional cytokine known to regulate cellular functions in contexts of injury and disease through its receptor, fibroblast growth factor–inducible molecule 14 (Fn14). Although many of the processes and downstream signals regulated by the TWEAK/Fn14 pathway have been implicated in the development of cardiac dysfunction, the role of TWEAK in the cardiovascular system is completely unknown.

Methods and Results— Herein, we demonstrate that mouse and human cardiomyocytes express the TWEAK receptor Fn14. Furthermore, we determine that elevated circulating levels of TWEAK, induced via transgenic or adenoviral-mediated gene expression in mice, result in dilated cardiomyopathy with subsequent severe cardiac dysfunction. This phenotype was mediated exclusively by the Fn14 receptor, independent of tumor necrosis factor-, and was associated with cardiomyocyte elongation and cardiac fibrosis but not cardiomyocyte apoptosis. Moreover, we find that circulating TWEAK levels were differentially upregulated in patients with idiopathic dilated cardiomyopathy compared with other forms of heart disease and normal control subjects.

Conclusions— Our data suggest that TWEAK/Fn14 may be important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy.

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CLINICAL PERSPECTIVE

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