Transgenic mice with cardiac-specific expression of activating transcription factor 3, a stress-inducible gene, have conduction abnormalities and contractile dysfunction

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 demo nstrate that expression of ATF3 is induced by cardiac ischemia coupled with reperfusion (ischemia-reperfusion) in both cultured cells and an animal mo del. Transgenic mice expressing ATF3 under the control of the alpha -myosin heavy chain promoter have atrial enlargement, and atrial and ventricular h ypertrophy. Microscopic examination showed myocyte degeneration and fibrosi s. Functionally, the transgenic heart has reduced contractility and aberran t conduction. Interestingly, expression of sorcin, a gene whose product inh ibits the release of calcium from sarcoplasmic reticulum, is increased in t hese transgenic hearts. Taken together, our results indicate that expressio n of ATF3, a stress-inducible gene, in the heart leads to altered gene expr ession and impaired cardiac function.