Details

Autor(en) / Beteiligte

• Gorog, Diana A.
• Jabr, Rita I.
• Tanno, Masaya
• Sarafraz, Negin
• Clark, James E.
• Fisher, Simon G.
• Cao, Xou Bin
• Bellahcene, Mohamed
• Dighe, Kushal
• Kabir, Alamgir M. N.
• Quinlan, Roy A.
• Kato, Kanefusa
• Gaestel, Matthias
• Marber, Michael S.
• Heads, Richard J.

Titel

MAPKAPK-2 Modulates p38-MAPK Localization and Small Heat Shock Protein Phosphorylation but Does Not Mediate the Injury Associated with p38-MAPK Activation during Myocardial Ischemia

Ist Teil von

• Cell stress & chaperones, 2009-09, Vol.14 (5), p.477-489

Ort / Verlag

Dordrecht: Springer

Erscheinungsjahr

2009

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• MAPKAPK-2 (MK2) is a protein kinase activated downstream of p38-MAPK which phosphorylates the small heat shock proteins HSP27 and αB crystallin and modulates p38-MAPK cellular distribution. p38-MAPK activation is thought to contribute to myocardial ischemic injury; therefore, we investigated MK2 effects on ischemic injury and p38 cellular localization using MK2-deficient mice (KO). Immunoblotting of extracts from Langendorff-perfused hearts subjected to aerobic perfusion or global ischemia or reperfusion showed that the total and phosphorylated p38 levels were significantly lower in $\text{MK}2^{-/-}$ compared to $\text{MK}2^{+/+}$ hearts at baseline, but the ratio of phosphorylated/total p38 was similar. These results were confirmed by cellular fractionation and immunoblotting for both cytosolic and nuclear compartments. Furthermore, HSP27 and αB crsytallin phosphorylation were reduced to baseline in $\text{MK}2^{-/-}$ hearts. On semiquantitative immunofluorescence laser confocal microscopy of hearts during aerobic perfusion, the mean total p38 fluorescence was significantly higher in the nuclear compared to extranuclear (cytoplasmic, sarcomeric, and sarcolemmal compartments) in $\text{MK}2^{+/+}$ hearts. However, although the increase in phosphorylated p38 fluorescence intensity in all compartments following ischemia in $\text{MK}2^{+/+}$ hearts was lost in $\text{MK}2^{-/-}$ hearts, it was basally elevated in nuclei of $\text{MK}2^{-/-}$ hearts and was similar to that seen during ischemia in $\text{MK}2^{+/+}$ hearts. Despite these differences, similar infarct volumes were recorded in wild-type $\text{MK}2^{+/+}$ and $\text{MK}2^{-/-}$ hearts, which were decreased by the p38 inhibitor SB203580 (1 μM) in both genotypes. In conclusion, p38 MAPK-induced myocardial ischemic injury is not modulated by MK2. However, the absence of MK2 perturbs the cellular distribution of p38. The preserved nuclear distribution of active p38 MAPK in $\text{MK}2^{-/-}$ hearts and the conserved response to SB203580 suggests that activation of p38 MAPK may contribute to injury independently of MK2.