Published Online
on April 6, 2009

A more recent version of this article appeared on April 21, 2009

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Submitted on November 20, 2008
Accepted on February 9, 2009

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^*, and 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.

^* To whom correspondence should be addressed. E-mail: rliao{at}rics.bwh.harvard.edu or linda.burkly{at}biogenidec.com.

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.

Key words: cardiomyocytes • heart failure • hypertrophy • Fn14 TWEAK receptor • Tweak protein, mouse

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