The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the ER stressor thapsigargin (TG), which depletes ER calcium, induced death of cultured neonatal rat ventricular myocytes (NRVMs) in high media volume but fostered protection in low media volume. In contrast, another ER stressor, tunicamycin (TM), a protein glycosylation inhibitor, induced NRVM death in all media volumes, suggesting that protective proteins were secreted in response to TG but not TM. Proteomic analyses of TG- and TM-conditioned media showed that the secretion of most proteins was inhibited by TG and TM; however, secretion of several ER-resident proteins, including GRP78 was increased by TG but not TM. Simulated ischemia, which decreases ER/SR calcium also increased secretion of these proteins. Mechanistically, secreted GRP78 was shown to enhance survival of NRVMs by collaborating with a cell-surface protein, CRIPTO, to activate protective AKT signaling and to inhibit death-promoting SMAD2 signaling. Thus, proteins secreted during ER stress mediated by ER calcium depletion can enhance cardiac myocyte viability.

Advanced Clinical Biosystems Research Institute Heart Institute and Department of Medicine Cedars Sinai Medical Center Los Angeles CA USA

Advanced Clinical Biosystems Research Institute Heart Institute and Department of Medicine Cedars Sinai Medical Center Los Angeles CA USA; Institute of Analytical Chemistry of the Czech Academy of Sciences Brno Czech Republic

Department of Internal Medicine 3 Partner Site Heidelberg Mannheim Germany

Department of Internal Medicine 3 Partner Site Heidelberg Mannheim Germany; Section of Bioinformatics and Systems Cardiology Klaus Tschira Institute for Integrative Computational Cardiology Heidelberg University Hospital Heidelberg Germany

San Diego State University Heart Institute and the Department of Biology San Diego State University San Diego CA USA

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