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(Circulation. 2005;112:1470-1477.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Lack of JunD Promotes Pressure Overload–Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart

Denise Hilfiker-Kleiner, PhD; Andres Hilfiker, PhD; Karol Kaminski, MD; Arnd Schaefer, MD; Joon-Keun Park, PhD; Kim Michel, BS; Anja Quint, BS; Moshe Yaniv, PhD; Jonathan B. Weitzman, PhD; Helmut Drexler, MD

From the Departments of Cardiology and Angiology (D.H.-K., K.K., A.S., K.M., A.Q., H.D.), Cardiovascular Surgery (A.H.), and Nephrology (J.P.), Hannover Medical School, Hannover, Germany; and Unit of Gene Expression and Disease, Pasteur Institute, Paris, France (M.Y., J.B.W.).

Correspondence to Denise Hilfiker-Kleiner, PhD, Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. E-mail hilfiker.denise{at}mh-hannover.de

Received November 18, 2004; revision received May 18, 2005; accepted June 7, 2005.

Background— The Jun family of activator protein 1 (AP-1) transcription factors (c-Jun, JunB, and JunD) is involved in fundamental biological processes such as proliferation, apoptosis, tumor angiogenesis, and hypertrophy. The role of individual AP-1 transcription factors in the stressed heart is not clear. In the present study we analyzed the role of JunD in survival, hypertrophy, and angiogenesis in the pressure-overloaded mouse heart after thoracic aortic constriction.

Methods and Results— Mice lacking JunD (knockout [KO]) showed increased mortality and enhanced cardiomyocyte apoptosis and fibrosis associated with increased levels of hypoxia-induced factor-1, vascular endothelial growth factor (VEGF), p53, and Bax protein and reduced levels of Bcl-2 protein after 7 days of severe pressure overload compared with wild-type (WT) siblings. Cardiomyocyte hypertrophy in surviving KO mice was enhanced compared with that in WT mice. Chronic moderate pressure overload for 12 weeks caused enhanced left ventricular hypertrophy in KO mice, and survival and interstitial fibrosis were comparable with WT mice. Cardiac function, 12 weeks after operation, was comparable among shams and pressure-overloaded mice of both genotypes. In addition, KO mice exposed to chronic pressure overload showed higher cardiac capillary density associated with increased protein levels of VEGF.

Conclusions— Thus, JunD limits cardiomyocyte hypertrophy and protects the pressure-overloaded heart from cardiac apoptosis. These beneficial effects of JunD, however, are associated with antiangiogenic properties.

Key Words: angiogenesis • apoptosis • hypertrophy

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