Intracellular signaling pathways control mitochondrial events associated with the development of ischemia/ reperfusion-associated damage.
Ischemia (I) and reperfusion (R) trigger a series of events, which culminate in severe injury to the transplanted organ. Cell death resulting from the formation of mitochondrial reactive oxygen species (ROS) coupled with the perturbation of mitochondrial Ca2+ homeostasis is central to the development of IR-associated tissue damage. We and others have shown recently that intracellular signaling pathways critically control these mitochondrial changes, making them potential targets for therapeutic intervention. Using a heterotopic murine heart transplant model as well as primary and immortalized cardiomyocyte cells we established the activity patterns of mitogen-activated protein kinases (MAPKs) ERK, JNK, and p38 during IR, and probed into their role in the perturbation of mitochondrial ROS and Ca2+ homeostasis, which are necessary for cardiomyocyte death. Our results showed a strong activation of all three MAPKs as well as a rise in mitochondrial ROS and Ca2+ during early reoxygenation. Inhibiting p38 kinase most efficiently prevented ROS production, Ca2+ overload and cell death, suggesting that targeting this signaling molecule may provide a possible strategy to limit the effects of IR.
Sucher
Robert
R
Daniel Swarovski Research Laboratory (DSL), Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University (IMU), Innsbruck, Austria.
Gehwolf
Philipp
P
Kaier
Thomas
T
Hermann
Martin
M
Maglione
Manuel
M
Oberhuber
Rupert
R
Ratschiller
Thomas
T
Kuznetsov
Andrey V
AV
Bösch
Florian
F
Kozlov
Andrey V
AV
Ashraf
Muhammad Imtiaz
MI
Schneeberger
Stefan
S
Brandacher
Gerald
G
Ollinger
Robert
R
Margreiter
Raimund
R
Troppmair
Jakob
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016027:Heart Transplantation; D000860:Hypoxia; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000473:pathology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen; D002118:Calcium