, Volume 21, Issue 11, pp 1227–1239 | Cite as

Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells

  • Eltyeb AbdelwahidEmail author
  • Haijie Li
  • Jianxin Wu
  • Ana Carolina Irioda
  • Katherine Athayde Teixeira de Carvalho
  • Xuelai LuoEmail author


Cardiomyocyte apoptosis is a major process in pathogenesis of a number of heart diseases, including ischemic heart diseases and cardiac failure. Ensuring survival of cardiac cells by blocking apoptotic events is an important strategy to improve cardiac function. Although the role of ER disruption in inducing apoptosis has been demonstrated, we do not yet fully understand how it influences the mitochondrial apoptotic machinery in cardiac cell models. Recent investigations have provided evidences that the prosurvival protein HCLS1-associated protein X-1 (Hax1) protein is intimately associated with the pathogenesis of heart disease, mitochondrial biology, and protection from apoptotic cell death. To study the role of Hax1 upon ER stress induction, Hax1 was overexpressed in cardiac cells subjected to ER stress, and cell death parameters as well as mitochondrial alterations were examined. Our results demonstrated that the Hax1 is significantly downregulated in cardiac cells upon ER stress induction. Moreover, overexpression of Hax1 protected from apoptotic events triggered by Tunicamycin-induced ER stress. Upon treatment with Tunicamycin, Hax1 protected from mitochondrial fission, downregulation of mitofusins 1 and 2 (MFN1 and MFN2), loss of mitochondrial membrane potential (∆Ψm), production of reactive oxygen species (ROS) and apoptotic cell death. Taken together, our results suggest that Hax1 inhibits ER stress-induced apoptosis at both the pre- and post-mitochondrial levels. These findings may offer an opportunity to develop new agents that inhibit cell death in the diseased heart.


Hax1 ER stress Mitochondria Mitofusin Mitochondrial fission ROS Apoptosis 



We thank Dr. Luca Pellegrini (Faculty of Medicine, Université Laval, Quebec, QC, Canada) for Hax1 overexpression construct, Dr. Thomas Simmen for discussion and Dr. Aikaterini Kontrogianni-Konstantopoulos for kindly sharing information on Hax1 expression. We are grateful to Mr. Denislam Zaripov for art drawing. E.A. was supported by the National Heart, Lung, and Blood Institute (NIH/NHLBI), Grant SP0012613. X.L. was supported by the National Natural Science Foundation of China (81272278). K.A.T.C was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) of Brazil, Grant PE 1711.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Eltyeb Abdelwahid
    • 1
    Email author
  • Haijie Li
    • 2
  • Jianxin Wu
    • 2
  • Ana Carolina Irioda
    • 3
  • Katherine Athayde Teixeira de Carvalho
    • 3
  • Xuelai Luo
    • 2
    Email author
  1. 1.Feinberg Cardiovascular Research Institute, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Cancer Research Institute, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.Pequeno Príncipe Faculty, Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe InstituteChild and Adolescent Health ResearchCuritibaBrazil

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