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Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise
Author(s) -
Golbidi S,
Botta A,
Gottfred S,
Nusrat A,
Laher I,
Ghosh S
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12847
Subject(s) - glutathione , programmed cell death , gclc , oxidative stress , necrosis , apoptosis , in vivo , reactive oxygen species , pharmacology , endocrinology , medicine , chemistry , biology , biochemistry , microbiology and biotechnology , enzyme
Background and Purpose The effect of antioxidants on ageing type 2 diabetic ( T 2 D ) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress ( mOXS ) and cell death in ageing db/db mice hearts. Experimental Approach The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro . Key Results During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis‐specific single‐stranded DNA breaks and necrosis‐specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH ‐regulated ‘switch’ in death phenotypes came from NIH ‐3 T 3 fibroblasts and H 9c2 cardiomyocytes treated with H 2 O 2 , a reactive oxygen species ( ROS ). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase ( GCLc ) protected fibroblasts and cardiomyocytes from necrosis induced by H 2 O 2 , but elevated caspase‐3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase‐3 activity, GCLc overexpression during staurosporine‐induced death, which was not characterized by ROS , increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH ‐mediated cytoprotection. Conclusions and Implications While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T 2 D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise.