Intracellular signaling pathways control mitochondrial events associated with the development of ischemia/ reperfusion-associated damage

Abstract

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.

Role of p38 inhibition in cardiac ischemia/reperfusion injury

“…In vitro treatment with a p38 inhibitor, mainly SB203580, prior to ischemia at concentrations ranging from 1 to 15 μM was found to protect the cardiac cells from ischemia/reperfusion injury, suggesting an undesired effect of p38 activation in myocardial ischemia/reperfusion [36,50,[54][55][56][57][58][59][60][61][62][63]. However, there have been some reports of beneficial effects following p38 activation, in which its activation could lead to the protection against injury rather than a harmful effect.…”

ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca2+ overload and contractile dysfunction via the JAK2/STAT3 pathway

“…ROS have been shown to be a causal factor for the development of Ca 2+ overload in cardiomyocytes during I/R injury [3,36]. However, ROS also act as a trigger to protect the heart from I/ R injury [2,4,5].…”

A young surgeon's experience with research in Europe and the USA

“…As a medical student at Innsbruck Medical University, I first encountered basic science and started research on intracellular signaling pathway activations during ischemia and reperfusion in solid organ transplantation and finished my M.D. thesis on this research project [4]. After clinical internships at the Royal College of Surgeons, the University of Sydney, and the University of Zurich where I was exposed to different academic systems and schemes, I started my surgical training at the Department of Visceral-, Transplant-and Thoracic Surgery in Innsbruck, Austria.…”