PMID- 32339566 OWN - NLM STAT- MEDLINE DCOM- 20210712 LR - 20211204 IS - 1095-8584 (Electronic) IS - 0022-2828 (Print) IS - 0022-2828 (Linking) VI - 143 DP - 2020 Jun TI - Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response. PG - 132-144 LID - S0022-2828(20)30094-8 [pii] LID - 10.1016/j.yjmcc.2020.04.012 [doi] AB - 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. CI - Copyright (c) 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Blackwood, Erik A AU - Blackwood EA AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Thuerauf, Donna J AU - Thuerauf DJ AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Stastna, Miroslava AU - Stastna M AD - 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. FAU - Stephens, Haley AU - Stephens H AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Sand, Zoe AU - Sand Z AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Pentoney, Amber AU - Pentoney A AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Azizi, Khalid AU - Azizi K AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Jakobi, Tobias AU - Jakobi T AD - Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany; Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, Heidelberg University Hospital, Heidelberg, Germany. FAU - Van Eyk, Jennifer E AU - Van Eyk JE AD - Advanced Clinical Biosystems Research Institute, Heart Institute and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Katus, Hugo A AU - Katus HA AD - Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany. FAU - Glembotski, Christopher C AU - Glembotski CC AD - San Diego State University Heart Institute and the Department of Biology, San Diego State University, San Diego, CA, USA. FAU - Doroudgar, Shirin AU - Doroudgar S AD - Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Germany. Electronic address: shirin.doroudgar@med.uni-heidelberg.de. LA - eng GR - R01 HL149931/HL/NHLBI NIH HHS/United States GR - R01 HL075573/HL/NHLBI NIH HHS/United States GR - F31 HL140850/HL/NHLBI NIH HHS/United States GR - F32 HL010026/HL/NHLBI NIH HHS/United States GR - P01 HL085577/HL/NHLBI NIH HHS/United States GR - R01 HL141463/HL/NHLBI NIH HHS/United States GR - P01 HL112730/HL/NHLBI NIH HHS/United States GR - R01 HL132075/HL/NHLBI NIH HHS/United States GR - R01 HL135893/HL/NHLBI NIH HHS/United States GR - R01 HL104535/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200425 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Biomarkers) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Hspa5 protein, mouse) RN - 0 (Membrane Glycoproteins) RN - 0 (Neoplasm Proteins) RN - 0 (Proteome) RN - 0 (Tdgf1 protein, mouse) RN - 62229-50-9 (Epidermal Growth Factor) RN - 67526-95-8 (Thapsigargin) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Apoptosis MH - Autocrine Communication MH - Biomarkers MH - Calcium/metabolism MH - Calcium Signaling/drug effects MH - Cell Survival MH - Cells, Cultured MH - Disease Susceptibility MH - Endoplasmic Reticulum Chaperone BiP MH - *Endoplasmic Reticulum Stress/drug effects MH - Epidermal Growth Factor/metabolism MH - Membrane Glycoproteins/metabolism MH - Mice MH - Myocytes, Cardiac/drug effects/*metabolism MH - Neoplasm Proteins/metabolism MH - Paracrine Communication MH - *Proteome MH - *Proteomics/methods MH - Rats MH - Sarcoplasmic Reticulum/metabolism MH - Signal Transduction/drug effects MH - Thapsigargin/pharmacology PMC - PMC8597053 MID - NIHMS1593476 OTO - NOTNLM OT - Cardiac myocyte death OT - Cardiokine OT - Cardioprotection OT - ER stress OT - Heart failure OT - Proteostasis COIS- Declaration of Competing Interest The authors declare that they have no conflict of interest. EDAT- 2020/04/28 06:00 MHDA- 2021/07/13 06:00 PMCR- 2021/11/17 CRDT- 2020/04/28 06:00 PHST- 2019/10/13 00:00 [received] PHST- 2020/04/07 00:00 [revised] PHST- 2020/04/09 00:00 [accepted] PHST- 2020/04/28 06:00 [pubmed] PHST- 2021/07/13 06:00 [medline] PHST- 2020/04/28 06:00 [entrez] PHST- 2021/11/17 00:00 [pmc-release] AID - S0022-2828(20)30094-8 [pii] AID - 10.1016/j.yjmcc.2020.04.012 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2020 Jun;143:132-144. doi: 10.1016/j.yjmcc.2020.04.012. Epub 2020 Apr 25.