The Transcription Factor ATF4 Promotes Expression of Cell Stress Genes and Cardiomyocyte Death in a Cellular Model of Atrial Fibrillation

INTRODUCTION: Cardiomyocyte remodelling in atrial fibrillation (AF) has been associated with both oxidative stress and endoplasmic reticulum (ER) stress and is accompanied by a complex transcriptional regulation. Here, we investigated the role the oxidative stress and ER stress responsive bZIP transcription factor ATF4 plays in atrial cardiomyocyte viability and AF induced gene expression. METHODS: HL-1 cardiomyocytes were subjected to rapid field stimulation. Forced expression of ATF4 was achieved by adenoviral gene transfer. Using global gene expression analysis and chromatin immunoprecipitation, ATF4 dependent transcriptional regulation was studied, and tissue specimen of AF patients was analysed by immunohistochemistry. RESULTS: Oxidative stress and ER stress caused a significant reduction in cardiomyocyte viability and were associated with an induction of ATF4. Accordingly, ATF4 was also induced by rapid field stimulation mimicking AF. Forced expression of wild type ATF4 promoted cardiomyocyte death. ATF4 was demonstrated to bind to the promoters of several cell stress genes and to induce the expression of a number of ATF4 dependent stress responsive genes. Moreover, immunohistochemical analyses showed that ATF4 is expressed in the nuclei of cardiomyocytes of tissue specimen obtained from AF patients. CONCLUSION: ATF4 is expressed in human atrial cardiomyocytes and is induced in response to different types of cell stress. High rate electrical field stimulation seems to result in ATF4 induction, and forced expression of ATF4 reduces cardiomyocyte viability

Merneptah’s ‘Israel’ and the Absence of Origins in Biblical Scholarship

This article examines the Merneptah Stele and its role in recent efforts to reconstruct Israelite history and identity. Though necessarily concerned with the issues of translation and location as they relate to the entity named in the stele, this review is dominated by an assessment of the various ways in which biblical scholarship has related to this singular reference. To that end, issues of theory and method, both archaeological and anthropological, are prioritized as the review appraises the various attempts to isolate this entity as the Archimedean point of Israelite historical and ethnic development. Though certainly critical of what it perceives as the sterile reproduction of long-held beliefs, it is a review that, in its appeal to the work of Pierre Bourdieu, looks to identify prospects for further study of the stele, rather than foreclose the very questions that it raises