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Circulation Research. 2004;95:187-195
Published online before print June 10, 2004, doi: 10.1161/01.RES.0000134921.50377.61
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(Circulation Research. 2004;95:187.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Signal Transducer and Activator of Transcription 3 Is Required for Myocardial Capillary Growth, Control of Interstitial Matrix Deposition, and Heart Protection From Ischemic Injury

Denise Hilfiker-Kleiner, Andres Hilfiker, Martin Fuchs, Karol Kaminski, Arnd Schaefer, Bernhard Schieffer, Anja Hillmer, Andreas Schmiedl, Zhaoping Ding, Edith Podewski, Eva Podewski, Valeria Poli, Michael D. Schneider, Rainer Schulz, Joon-Keun Park, Kai C. Wollert, Helmut Drexler

From the Departments of Cardiology and Angiology (D.H.-K., A. Hilfiker, M.F., K.K., A. Schaefer, B.S., A. Hillmer, Edith Podewski, Eva Podewski, K.C.W., H.D.), Anatomy (A. Schmiedl), and Nephrology (J.-K.P.), Medical School Hannover, Germany; Institute for Cardiovascular Physiology (Z.D.), University of Düsseldorf, Germany; Department of Genetics, Biology, and Biochemistry (V.P.), University of Turin, Italy; Department of Medicine (M.D.S.), Baylor College of Medicine, Houston, Tex; Department of Pathophysiology (R.S.), Universitätsklinikum, Essen, Germany.

Correspondence to Helmut Drexler, MD, Abt Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str 1, 30625 Hannover, Germany. E-mail drexler.helmut{at}mh-hannover.de

The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure.


Key Words: mouse • signal transduction • angiogenesis • ischemia • heart failure




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