Geldanamycin prevents hemorrhage-induced ATP loss by overexpressing inducible HSP70 and activating pyruvate dehydrogenase.
Hemorrhage in mice results in decreased ATP levels in the jejunum, lung, kidney, heart, and brain but not in liver tissue lysates, albeit at variable levels and time kinetics. The decreased protein expression and activity of pyruvate dehydrogenase (PDH) accounted for the hemorrhage-induced ATP loss. Treatment with geldanamycin (GA; 1 microg/g body wt), a known inducer of heat shock protein (HSP)70, inhibited the hemorrhage-induced ATP loss in the jejunum, lung, heart, kidney, and brain. GA was found to increase PDH protein, preserve PDH enzymatic activity, and inhibit mucosal injury in jejunum tissues. GA-induced HSP70i was found to form complexes with PDH protein. HSP70 gene transfer into intestinal epithelial cells promoted PDH and ATP levels, whereas HSP70 short interfering RNA limited them. We conclude that agents able to increase the expression of HSP70 and PDH may be of value in reducing pathology resulting from hemorrhage-associated ATP loss.
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. Juliann.Kiang@na.amedd.army.mil
Juliann G
JG
Kiang
Phillip D
PD
Bowman
Xinyue
X
Lu
Yansong
Y
Li
Xuan Z
XZ
Ding
Baiteng
B
Zhao
Yuang-Taung
YT
Juang
James L
JL
Atkins
George C
GC
Tsokos
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006470:Hemorrhage / Q000378:metabolism* / Q000517:prevention & control*; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000378:metabolism* / Q000517:prevention & control*; D009928:Organ Specificity; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011809:Quinones / Q000008:administration & dosage*; D014018:Tissue Distribution; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011768:Pyruvate Dehydrogenase Complex; D011809:Quinones; D000255:Adenosine Triphosphate; C001277:geldanamycin