Increased efflux of glutathione conjugate in acutely diabetic cardiomyocytes.
In diabetes, cell death and resultant cardiomyopathy have been linked to oxidative stress and depletion of antioxidants like glutathione (GSH). Although the de novo synthesis and recycling of GSH have been extensively studied in the chronically diabetic heart, their contribution in modulating cardiac oxidative stress in acute diabetes has been largely ignored. Additionally, the possible contribution of cellular efflux in regulating GSH levels during diabetes is unknown. We used streptozotocin to make Wistar rats acutely diabetic and after 4 days examined the different processes that regulate cardiac GSH. Reduction in myocyte GSH in diabetic rats was accompanied by increased oxidative stress, excessive reactive oxygen species, and an elevated apoptotic cell death. The effect on GSH was not associated with any change in either synthesis or recycling, as both gamma-glutamylcysteine synthetase gene expression (responsible for bio syn thesis) and glutathione reductase activity (involved with GSH recycling) remained unchanged. However, gene expression of multidrug resistance protein 1, a transporter implicated in effluxing GSH during oxidative stress, was elevated. GSH conjugate efflux mediated by multidrug resistance protein 1 also increased in diabetic cardiomyocytes, an effect that was blocked using MK-571, a specific inhibitor of this transporter. As MK-571 also decreased oxidative stress in diabetic cardiomyocytes, an important role can be proposed for this transporter in GSH and reactive oxygen species homeostasis in the acutely diabetic heart.
Ghosh
Sanjoy
S
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of Bristish Columbia, Vancouver, Canada.
Ting
Simon
S
Lau
Howard
H
Pulinilkunnil
Thomas
T
An
Ding
D
Qi
Dake
D
Abrahani
Mohammed A
MA
Rodrigues
Brian
B
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1