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(Circulation. 2004;110:2631-2637.)
© 2004 American Heart Association, Inc.

Heart Failure

Pressure Overload Induces Cardiac Dysfunction and Dilation in Signal Transducer and Activator of Transcription 6–Deficient Mice

Shungo Hikoso, MD; Osamu Yamaguchi, MD, PhD; Yoshiharu Higuchi, MD, PhD; Shinichi Hirotani, MD, PhD; Toshihiro Takeda, MD; Kazunori Kashiwase, MD; Tetsuya Watanabe, MD; Masayuki Taniike, MD; Ikuko Tsujimoto, DMD; Michio Asahi, MD, PhD; Yasushi Matsumura, MD, PhD; Kazuhiko Nishida, MD, PhD; Hiroshi Nakajima, MD, PhD; Shizuo Akira, MD, PhD; Masatsugu Hori, MD, PhD; Kinya Otsu, MD, PhD

From the Department of Internal Medicine and Therapeutics (S.H., O.Y., Y.H., S.H., T.T., K.K., T.W., M.T., M.A., K.N., M.H., K.O.), Graduate School of Medicine; First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry (I.T.); Department of Medical Information Science (Y.M.), Graduate School of Medicine; and Department of Host Defense (S.A.), Research Institute for Microbial Disease, Osaka University, Suita, Osaka; and Department of Internal Medicine II, Graduate School of Medicine, Chiba University, Chiba (H.N.), Japan.

Correspondence to Kinya Otsu, MD, PhD, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail kotsu{at}medone.med.osaka-u.ac.jp

Received June 21, 2004; revision received August 18, 2004; accepted August 24, 2004.

Background— Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6^–/–) mice to examine the in vivo role of STAT6.

Methods and Results— STAT6^–/– hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6^–/– mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase–mediated biotin dUTP nick-end labeling–positive myocytes after TAC had increased in STAT6^–/– compared with wild-type mice. Prolonged induction of tumor necrosis factor- (TNF-) mRNA was observed in STAT6^–/– hearts, whereas TNF- mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6^–/– mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6^–/– cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6^–/– cardiomyocytes was rescued by forced expression of STAT6.

Conclusions— STAT6 plays a protective role against hemodynamic stress in hearts.

Key Words: heart failure • signal transduction • immune system

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