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Cardiomyocyte specific overexpression of C3orf58 activates ER stress leading to impaired cardiac function
Author(s) -
Zhang Zhiping,
Mirotsou Maria,
Payne Alan,
Mu Hui,
Zhang Lunan,
Finch Elizabeth A,
Pratt Richard E,
Rosenberg Paul,
Dzau Victor J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.929.7
Subject(s) - unfolded protein response , thapsigargin , tunicamycin , endocrinology , genetically modified mouse , medicine , microbiology and biotechnology , endoplasmic reticulum , transgene , regulator , biology , ryanodine receptor , chemistry , biochemistry , gene
Although accumulating evidence supports the crucial role of ER stress in cardiovascular diseases, essential information is still required for its role in the pathogenesis of these disorders. We previously reported the identification of C3orf58 (aka HASF) as a novel stem cell derived factor involved in cytoprotection. Transgenic mice with a high‐level of cardiac specific overexpression of HASF showed reduced fractional shortening as early as 4 weeks old. Neonatal cardiomyocytes isolated from these mice showed reduction in basal Ca 2+ levels, abnormal calcium oscillation and a dramatic reduction in magnitude of store‐operated Ca 2+ entry after stimulation. Adult transgenic cardiomyocytes exhibited reduced L type channel currents. Notable, all three pathways involved in ER stress, PERK, ATF6 and IRE1, were activated in the hearts of transgenic mice as early as 2 weeks old. Moreover, to demonstrate the specific effect of HASF on ER stress, fibroblasts isolated from HASF heterologous KO were treated with ER stress inducers thapsigargin and tunicamycin. The induction of ER stress sensor GPR78 was significantly lower in these treated fibroblasts. Based on our findings we propose that C3orf58 is a novel regulator of ER stress pathways whose overexpression is involved in cardiac pathology and disease. The study was supported by NHLBI/NIH grants RO1 HL35610, HL81744, HL72010, HL73219 and Foundation Leducq (to VJD).