TY - JOUR
T1 - Proteomic analysis of the cardiac myocyte secretome reveals extracellular protective functions for the ER stress response
AU - Blackwood, Erik A.
AU - Thuerauf, Donna J.
AU - Stastna, Miroslava
AU - Stephens, Haley
AU - Sand, Zoe
AU - Pentoney, Amber
AU - Azizi, Khalid
AU - Jakobi, Tobias
AU - Van Eyk, Jennifer E.
AU - Katus, Hugo A.
AU - Glembotski, Christopher C.
AU - Doroudgar, Shirin
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/6
Y1 - 2020/6
N2 - 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.
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.
KW - Cardiac myocyte death
KW - Cardiokine
KW - Cardioprotection
KW - ER stress
KW - Heart failure
KW - Proteostasis
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U2 - 10.1016/j.yjmcc.2020.04.012
DO - 10.1016/j.yjmcc.2020.04.012
M3 - Article
C2 - 32339566
AN - SCOPUS:85084362964
SN - 0022-2828
VL - 143
SP - 132
EP - 144
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -