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Tunicamycin‐induced ER Stress Effect on Cardiac Contractility
Author(s) -
Alabdaljabar Mohamad Saleh,
Valencia Sara Osorio,
Han Young Soo,
Sieck Gary C.
Publication year - 2019
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.2019.33.1_supplement.lb598
Subject(s) - tunicamycin , unfolded protein response , endoplasmic reticulum , myofilament , chemistry , medicine , endocrinology , contractility , dephosphorylation , microbiology and biotechnology , phosphorylation , biophysics , biology , biochemistry , myocyte , phosphatase
In cardiomyocytes, the endoplasmic reticulum (ER) plays a dynamic role in excitation‐contraction coupling by regulating cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ). Under pathological conditions the ER accumulates unfolded proteins triggering a homeostatic ER stress response to minimize and limit protein unfolding (via chaperone proteins) and accumulation (by decreasing synthesis and increasing degradation). The interactions between ER stress, [Ca 2+ ] cyt regulation and downstream contractile responses remain unknown, although such interactions may underlie the etiology of various cardiovascular diseases. We hypothesized that in cardiomyocytes ER stress alters the regulation of [Ca 2+ ] cyt and reduces cardiac contractility by decreasing myofilament Ca 2+ sensitivity. In isolated rat cardiomyocytes, ER stress was induced by tunicamycin, a naturally occurring antibiotic that induces ER stress by inhibiting N‐linked glycosylation. In one set of experiments, we used Western blotting techniques to evaluate the effects of ER stress on phosphorylation of cTnI at Ser23/24. In a second set of experiments, we evaluated the impact of tunicamycin on excitation‐contraction coupling by simultaneously measuring [Ca 2+ ] cyt (using Fura‐2 AM ratiometric imaging) and contractile (sarcomere length (SL) shortening) responses to electrical field stimulation using an IonOptix system. Tunicamycin induced an increase in phosphorylation of cTnI by 3–6 h. The evoked [Ca 2+ ] cyt transient was relatively unaffected by tunicamycin while the contractile response was markedly reduced. This resulted in a rightward shift in the phase loop relationship between [Ca 2+ ] cyt and SL shortening indicating reduced myofilament Ca 2+ sensitivity. We conclude that ER stress may underlie contractile dysfunction in a variety of cardiac diseases. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .