title: Endoplasmic reticulum resident protein 44 (ERp44) deficiency in mice and zebrafish leads to cardiac developmental and functional defects.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Ding-Yan
authors.initials: DY
authors.lastname: Wang
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Abbasi
authors.affiliation: Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.) Keenan Research Center for Biomedical Science and Zebrafish Center for Advanced Drug Discovery, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada (S.E.R., X.Y.W.).
authors.forename: Suzan
authors.initials: S
authors.lastname: El-Rass
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Jamie Yuanjun
authors.initials: JY
authors.lastname: Li
authors.affiliation: Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.).
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.affiliation: Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.).
authors.forename: Kotaro
authors.initials: K
authors.lastname: Naito
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Parveen
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bousette
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.) Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.).
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.).
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.) Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.) Keenan Research Center for Biomedical Science and Zebrafish Center for Advanced Drug Discovery, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada (S.E.R., X.Y.W.).
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.) Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.).
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Toronto, Ontario, Canada (D.Y.W., C.A., J.Y.L., P.S., N.B., S.S., P.H.B., B.C., X.Y.W., P.P.L., A.O.G.) Faculty of Medicine and Institute of Medical Science, University of Toronto, Ontario, Canada (S.E.R., F.D., K.N., P.H.B., X.Y.W., P.P.L., A.O.G.).
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Gramolini
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C520556:ERp44 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins
keywords: Ca2+; ERp44−/−; ESC‐derived cardiomyocytes; apoptosis; heart development and cardiomyopathy