ZFIN ID: ZDB-PUB-141022-5
Endoplasmic Reticulum Resident Protein 44 (ERp44) Deficiency in Mice and Zebrafish Leads to Cardiac Developmental and Functional Defects
Wang, D.Y., Abbasi, C., El-Rass, S., Li, J.Y., Dawood, F., Naito, K., Sharma, P., Bousette, N., Singh, S., Backx, P.H., Cox, B., Wen, X.Y., Liu, P.P., Gramolini, A.O.
Date: 2014
Source: Journal of the American Heart Association   3(5): 12256-64 (Journal)
Registered Authors:
Keywords: Ca2+, ERp44−/−, ESC‐derived cardiomyocytes, apoptosis, heart development and cardiomyopathy
MeSH Terms:
  • Animals
  • Apoptosis
  • Calcium Signaling
  • Cells, Cultured
  • Embryonic Stem Cells/metabolism*
  • Embryonic Stem Cells/pathology
  • Endoplasmic Reticulum/metabolism*
  • Endoplasmic Reticulum/pathology
  • Endoplasmic Reticulum Stress
  • Heart Defects, Congenital/embryology
  • Heart Defects, Congenital/genetics
  • Heart Defects, Congenital/metabolism*
  • Heart Defects, Congenital/pathology
  • Heart Defects, Congenital/physiopathology
  • Membrane Proteins/deficiency
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart/metabolism
  • Molecular Chaperones/genetics
  • Molecular Chaperones/metabolism*
  • Morphogenesis
  • Myocardial Contraction
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Phenotype
  • Reactive Oxygen Species/metabolism
  • Time Factors
  • Zebrafish/embryology
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 25332179 Full text @ J. Am. Heart Assoc.
Endoplasmic reticulum (ER) resident protein 44 (ERp44) 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 ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac development and function in mice, zebrafish, and embryonic stem cell (ESC)-derived cardiomyocytes to determine the underlying role of ERp44.
We generated and characterized ERp44(-/-) mice, ERp44 morphant zebrafish embryos, and ERp44(-/-) ESC-derived cardiomyocytes. Deletion of ERp44 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 ERp44(+/-) 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 ERp44 in the adult heart, in which high expression of ERp44 was observed in the outer subepicardial region of the myocardium.
ERp44 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.