Journal
CURRENT NEUROVASCULAR RESEARCH
Volume 6, Issue 4, Pages 267-278Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720209789630348
Keywords
Human brain endothelial cells; GSH/GSSG redox status; mitochondrial apoptotic signaling; mitochondrial permeability transition pore; methylglyoxal-induced apoptosis; biguanides; AMP-activated protein kinase activator; glitazones; insulin sensitizers and endothelial cell apoptosis
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Funding
- National Institutes of Health [DK44510]
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Oxidative stress-induced cerebral endothelial cell dysfunction is associated with cerebral microvascular complication of primary diabetic encephaolopathy, a neurodegenerative disorder of long-standing diabetes, but the injury mechanisms are poorly understood. This study sought to determine the contribution of carbonyl ( methylglyoxal, MG) stress to human brain endothelial cell (IHEC) apoptosis, the relationship to cellular redox status and mitochondrial membrane potential, and the protection by thiol antioxidant and insulin sensitizers. MG exposure induced IHEC apoptosis in association with perturbed cellular glutathione (GSH) redox status, decreased mitochondrial membrane potential ( m), activation of caspase-9 and -3, and cleavage of polyADP-ribose polymerase. Insulin sensitizers such as biguanides or AMP-activated protein kinase activator, but not glitazones, afforded cytoprotection through preventing m collapse and activation of caspase-9 that was independent of cellular GSH. Similarly, cyclosporine A prevented m collapse, while N-acetylcysteine (NAC) mediated the recovery of cellular GSH redox balance that secondarily preserved m. Collectively, these results provide mechanistic insights into the role of GSH redox status and mitochondrial potential in carbonyl stress-induced apoptosis of brain endothelial cells, with implications for cerebral microvascular complications associated with primary diabetic encephalopathy. The findings that thiol antioxidant and insulin sensitizers afforded cytoprotection suggest potential therapeutic approaches.
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