title: Endoplasmic reticulum (ER) stress triggers Hax1-dependent mitochondrial apoptotic events in cardiac cells.
abstract: 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.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL, 60611, USA. Eltyeb.abdelwahid@northwestern.edu.
authors.forename: Eltyeb
authors.initials: E
authors.lastname: Abdelwahid
authors.affiliation: Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430000, China.
authors.forename: Haijie
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430000, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Pequeno Príncipe Faculty, Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research, Av. Silva Jardim 1632, Box 80.250-200, Curitiba, Paraná, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Irioda
authors.affiliation: Pequeno Príncipe Faculty, Cell Therapy and Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research, Av. Silva Jardim 1632, Box 80.250-200, Curitiba, Paraná, Brazil.
authors.forename: Katherine Athayde Teixeira
authors.initials: KA
authors.lastname: de Carvalho
authors.affiliation: Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430000, China. luoxl@tjh.tjmu.edu.cn.
authors.forename: Xuelai
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C510653:Hax1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species
keywords: Apoptosis; ER stress; Hax1; Mitochondria; Mitochondrial fission; Mitofusin; ROS