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Protein O‐GlcNAcylation – A Novel Cell Survival Signal in Cardiac Stem Cells
Author(s) -
Zafir Ayesha,
Li Qianhong,
Bolli Roberto,
Jones Steven P.
Publication year - 2012
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.26.1_supplement.693.1
Subject(s) - stem cell , progenitor cell , hypoxia (environmental) , apoptosis , cancer research , in vivo , cell , microbiology and biotechnology , caspase 3 , caspase , programmed cell death , chemistry , biology , biochemistry , oxygen , organic chemistry
Background Clinical trials demonstrate the potential efficacy of stem/progenitor cell therapy in the post‐infarcted heart. Yet, the basic biology of these cells remains largely unexplored. Here, we demonstrate that protein O‐GlcNAcylation exerts a pro‐survival role in cardiac stem cells (CSCs). Methods/Results Lin − /c‐kit + CSCs sorted from the adult mouse heart responded to hypoxia‐reoxygenation by increasing protein OGlcNAcylation in a time‐dependent manner upon reoxygenation, along with significantly increased LDH release and caspase‐3/7 activity. We pharmacologically manipulated O‐GlcNAc levels in CSCs with loss‐ and gain‐of‐function approaches, i.e., inhibition of OGT (adds the O‐GlcNAc modification to proteins) by TT04 (0.001 mM), or inhibition of OGA (removes O‐GlcNAc) by ThG (0.025 mM) and subjected them to 3 h hypoxia, followed by 3 h reoxygenation. Reduction in protein O‐GlcNAcylation (via TT04) significantly exacerbated post‐hypoxic cell death (assessed by LDH release, MTS reduction, PI positivity), whereas augmenting O‐GlcNAc levels (via ThG) enhanced cell survival. Diminished OGlcNAc levels render CSCs more susceptible to the onset of post‐hypoxic apoptotic processes via elevated PARP cleavage by significantly enhanced caspase‐3/7 activation, whereas increasing O‐GlcNAcylation serves as a pre‐emptive pro‐survival signal in CSCs by significantly reducing caspase‐3/7 activity and cleaved PARP. Conclusions Protein O‐GlcNAcylation represents a robust pro‐survival signal during hypoxia‐reoxygenation injury in CSCs and could be exploited to enhance cell survival prior to in vivo stem cell transplantation for myocardial infarction. Financial support: NIH, AHA.*: p <0.05 vs. Normoxia Veh; #: p <0.05 vs. H/R Veh; n≥5/group