A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury

Abstract

BackgroundMany diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects.ResultsHere we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death.ConclusionsThese data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.

Targeting the molecular mechanisms of ischemic damage: Protective effects of alpha-crystallin-B

“…Our results suggest that hypoxia induces both the phosphorylation and oligomerization of cryab. It has been shown that cryab serine 59 phosphorylation is catalyzed by MAPKAP kinase-2 [40], effector of the p38MAPK pathway that has been previously suggested as an important mechanism triggering I/R injury through the elevation of mitochondrial ROS levels [41].…”

Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

“…Immunoblotting was performed, as described previously 32, with antibodies specific for cleaved caspase 3 (9664; Cell Signaling Technology, Boston, MA). Antibody complexes were visualized using ECL (Amersham, Buckinghamshire, UK) and quantified by using ImageJ software (National Institutes of Health, Bethesda, MD).…”

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

“…Excessive ROS production is one of the hallmarks of ischemia reperfusion injury particularly during the early phase of reperfusion, leading to oxidative stress, which further contributes to tissue damage [70]. Among potential sources of ROS, NOX1, NOX2 and NOX4 are the major ROS producing oxidases in the kidney [71][72][73][74].…”