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(American Journal of Pathology. 2001;159:639-650.)
© 2001 American Society for Investigative Pathology

Regular Articles

Transgenic Mice with Cardiac-Specific Expression of Activating Transcription Factor 3, a Stress-Inducible Gene, Have Conduction Abnormalities and Contractile Dysfunction

Yoshichika Okamoto*{dagger}, Alysia Chaves{ddagger}, Jingchun Chen*{dagger}§, Robert Kelley*, Keith Jones**, Harrison G. Weed, Kevin L. Gardner{dagger}{dagger}, Lisa Gangi{dagger}{dagger}, Mamoru Yamaguchi||, Wuthichai Klomkleaw||, Tomohiro Nakayama||, Robert L. Hamlin||, Cynthia Carnes{ddagger}, Ruth Altschuld*§, John Bauer{ddagger} and Tsonwin Hai*{dagger}§

From the Department of Molecular and Cellular Biochemistry,*
the Neurobiotechnology Center,{dagger}
the Department of Pharmacy,{ddagger}
the Ohio State Biochemistry Program,§
the Department of Medicine,
and the Department of Veterinary Biosciences,||
Ohio State University, Columbus, Ohio; the Department of Pharmacology and Cell Biophysics,**
University of Cincinnati, Cincinnati, Ohio; and the Advanced Technology Center,{dagger}{dagger}
National Cancer Institute, Gaithersburg, Maryland

Activating transcription factor 3 (ATF3) is a member of the CREB/ATF family of transcription factors. Previously, we demonstrated that the expression of the ATF3 gene is induced by many stress signals. In this report, we demonstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal model. Transgenic mice expressing ATF3 under the control of the {alpha}-myosin heavy chain promoter have atrial enlargement, and atrial and ventricular hypertrophy. Microscopic examination showed myocyte degeneration and fibrosis. Functionally, the transgenic heart has reduced contractility and aberrant conduction. Interestingly, expression of sorcin, a gene whose product inhibits the release of calcium from sarcoplasmic reticulum, is increased in these transgenic hearts. Taken together, our results indicate that expression of ATF3, a stress-inducible gene, in the heart leads to altered gene expression and impaired cardiac function.




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