The role of mitogen activated protein kinase activated protein kinase-2 in regulating p38 mitogen activated protein kinase induced cyclooxygenase-2 induction and heart failure

Investigation into the etiology of heart failure has revealed a complex network of signaling molecules that induce the characteristics of the disease. One such family of molecules are the Mitogen Activated Protein Kinases (MAPK), of which p38 MAPK is activated in stressed myocardium and induces inflammation, hypertrophy and other heart failure related effects. However, little of the up- and downstream regulators of p38 activity are known. Here we investigate the role of the downstream p38 target kinase MAPK Activated Protein Kinase-2 (MK2) in p38 related cyclooxygenase-2 (COX-2) induction and heart failure. By inducing MK2 activity by adenoviral constructs in primary rat heart cells and knocking out (KO) MK2 in primary embryonic fibroblasts, we were able to demonstrate by quantitative polymerase chain reaction (qPCR) and Western blot that MK2 promotes COX-2 protein levels without altering COX-2 mRNA. These findings were shown to have in vivo relevance after replicating them in stimulated hearts of MK2 wild type (WT) and KO mice. We further confirmed by in vitro radioactive methionine labeling that MK2 may have a novel role in specifically promoting COX-2 translation without altering degradation. To further investigate the role of COX-2 in subsequent heart pathology, we established a cardiac specific transgenic (Tg) COX-2 mouse model using the cre-LoxP gene switch. These mice had normal cardiac function as assessed by echocardiography and pressure catheterization. However, we showed by histological methods and qPCR that TgCOX-2 mice overexpress functional COX-2 and develop mild hypertrophy associated with stress gene activation. Lastly, in order to investigate the role of MK2 in p38 mediated heart failure, we bred heart specific p38 activated mice into the MK2 KO background. The MK2 KO background significantly improved survival in these mice, while improving some but not all aspects of pathologic function and remodeling as measured by echocardiography and pressure catheterization. Furthermore, MK2 KO did not alter stress gene activation in these mice as measured by qPCR. In summary, we have demonstrated that the downstream p38 MAPK target kinase MK2 has a novel role in promoting COX-2 translation in the heart, and that COX-2 itself can promote mild pathology and stress gene activation. We also have shown that MK2 has a role in carrying out some, but not all, aspects of p38 induced heart failure.