Glucose exacerbates zinc-induced astrocyte death.
Zinc and cytosolic phospholipase A(2) (cPLA(2)) have been implicated in the death of neural cells and the pathogenesis of ischemia, and hyperglycemia is a potential augmenting factor. However, their potential crosstalk and/or interaction in mediating cell damage have not yet been fully elucidated. Here, we report that a potential link between cPLA(2) activation and zinc-induced astrocyte damage involving reactive oxygen species (ROS)/protein kinase C-α (PKC-α)/extracellular signal-regulated kinase (ERK) signaling and glucose is able to increase zinc uptake and potentiate zinc-induced alterations and astrocyte damage. The cell death caused by ZnCl(2) was accompanied by increased ROS generation, PKC-α membrane translocation, ERK phosphorylation, and cPLA(2) phosphorylation and activity. Pharmacological studies revealed that these activations contributed to ZnCl(2)-induced astrocyte death. Mechanistic studies had suggested that ROS/PKC-α/ERK was a potential signal linking zinc and cPLA(2). Glucose increased zinc uptake and potentiated ZnCl(2)-induced alterations and astrocyte death. These observations indicated that ROS/PKC-α/ERK signaling and cPLA(2) were actively involved in zinc-induced astrocyte damage, and suggested zinc was a potential downstream effector in hyperglycemia-aggravated astrocyte injury.
Chang
Cheng-Yi
CY
Department of Surgery, Fong Yuan Hospital, Taichung, Taiwan.
Ou
Yen-Chuan
YC
Kao
Tsung-Kuei
TK
Pan
Hung-Chuan
HC
Lin
Shih-Yi
SY
Liao
Su-Lan
SL
Wang
Wen-Yi
WY
Lu
Hsi-Chi
HC
Chen
Chun-Jung
CJ
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017967:Zinc Compounds / Q000633:toxicity*
D002712:Chlorides; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C016837:zinc chloride; D007770:L-Lactate Dehydrogenase; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D054467:Phospholipases A2; D005947:Glucose