Activation of AMP-activated protein kinase mediates acute and severe hypoxic injury to pancreatic beta cells.
In islet transplantation, a substantial part of the graft becomes nonfunctional for several reasons including hypoxia. AMP-activated protein kinase (AMPK) in mammalian cells is a regulator of energy homeostasis, and is activated by metabolic stresses such as hypoxia. However, the role of AMPK in hypoxic injury to pancreatic beta cells is not clear. When a rat beta cell line, INS-1 cell, was incubated in an anoxic chamber, phosphorylation of both AMPK and its downstream protein, acetyl-CoA carboxylase 2 increased with time. Adenovirus-mediated expression of constitutively active form of AMPK under normoxic conditions increased caspase-3 activation, suggesting induction of apoptosis. Reactive oxygen species production also increased with time during hypoxia. Pretreatment with compound C, an AMPK inhibitor, or N-acetyl-l-cysteine, an antioxidant, significantly lowered hypoxia-mediated cell death. These results suggest that AMPK, in association with oxidative stress, plays an important role in acute and severe hypoxic injury to pancreatic beta cells.
Ryu
Gyeong Ryul
GR
Division of Endocrinology & Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Lee
Min-Kyung
MK
Lee
Esder
E
Ko
Seung-Hyun
SH
Ahn
Yu-Bae
YB
Kim
Ji-Won
JW
Yoon
Kun-Ho
KH
Song
Ki-Ho
KH
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D055372:AMP-Activated Protein Kinases