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GGF2 Activation of PI3 kinase Pathway Mediates Cardiomyocyte Protection via Effects on Mitochondria
Author(s) -
Srinivas Maya,
Cao Jing,
Sarmiere Patrick,
Caggiano Anthony,
Button Donald
Publication year - 2015
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.29.1_supplement.728.48
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , mapk/erk pathway , mitochondrion , kinase , apoptosis , protein kinase b , doxorubicin , signal transduction , erbb , mtt assay , biology , chemistry , pharmacology , biochemistry , genetics , chemotherapy
Glial growth is a neuregulin‐1 isoform that mediates ERBB receptor signaling. It has been shown to improve left ventricular function in several models of heart failure, though the mechanisms are poorly understood. GGF2 regulates PI3 kinase (PI3K) and MAP kinase (MAPK) as measured by pAKT and pERK1/2 formation in numerous cardiomyocyte models, including HL‐1, neonatal rat ventricular myocytes and human iPSC‐derived cardiomyocytes. To better understand GGF2 action in the stressed heart, we have developed in vitro systems to study GGF2 protection of cardiomyocytes from doxorubicin induced toxicity associated with mitochondrial metabolic status, membrane potential and apoptosis. MTT labeling index was used as an endpoint measurement of viability. Doxorubicin decreases the MTT labeling index to 20% while GGF2 reverses this toxicity to nearly 50% of the labeling in untreated cells with an EC 50 of ~80 pM. This effect appears to be more dependent upon AKT signaling than MAPK as assessed using signaling pathway inhibitors. Doxorubicin's cytotoxicity involves alteration of mitochondrial membrane potential (Δψm) and can be monitored using the voltage‐dependent dye, JC‐10. We used JC‐10 to reveal that GGF2 pre‐treatment improves Δψm in stressed cells. Mitochondrial dysfunction is closely associated with caspase activation. While caspase3/7 activity increases with doxorubicin, GGF2 prevents or delays onset of caspase activation. Our results demonstrate GGF2 has cytoprotective actions in HL‐1 cells that require PI3K activation and involves maintenance of Δψm. Current efforts are aimed at elucidating the roles for PI3K‐dependent GGF2 regulation of mitochondrial function, and identifying the genes that may be responsible for this effect.