Endoplasmic Reticulum Resident Protein 44 (ERp44) Deficiency in Mice and Zebrafish Leads to Cardiac Developmental and Functional Defects

Background Endoplasmic reticulum ( ER ) resident protein 44 ( ER p44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca 2+ homeostasis. However, the role of ER p44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ER p44 in cardiac development and function in mice, zebrafish, and embryonic stem cell ( ESC )‐derived cardiomyocytes to determine the underlying role of ER p44. Methods and Results We generated and characterized ER p44 −/− mice, ER p44 morphant zebrafish embryos, and ER p44 −/− ESC ‐derived cardiomyocytes. Deletion of ER p44 in mouse and zebrafish caused significant embryonic lethality, abnormal heart development, altered Ca 2+ dynamics, reactive oxygen species generation, activated ER stress gene profiles, and apoptotic cell death. We also determined the cardiac phenotype in pressure overloaded, aortic‐banded ER p44 +/− mice: enhanced ER stress activation and increased mortality, as well as diastolic cardiac dysfunction with a significantly lower fractional shortening. Confocal and LacZ histochemical staining showed a significant transmural gradient for ER p44 in the adult heart, in which high expression of ER p44 was observed in the outer subepicardial region of the myocardium. Conclusions ER p44 plays a critical role in embryonic heart development and is crucial in regulating cardiac cell Ca 2+ signaling, ER stress, ROS ‐induced oxidative stress, and activation of the intrinsic mitochondrial apoptosis pathway.