MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice

Abstract

AbstractBackground:Altering the onset, intensity, or duration of inflammation can impact the recovering heart’s structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. This study was to determine if MK2-deficiency impaired the inflammatory phase of post-MI wound repair.Methods and Results:Myocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2+/+and MK2-/-littermate mice. Five days post-MI, survival was 100% in MI-MK2-/-(n = 20) and 79% in MI-MK2+/+mice (n = 29; Mandel-Cox test:P< 0.05). Area at risk and infarct size were similar. Echocardiographic imaging revealed that both systolic and diastolic LV diameters were greater in MI-MK2+/+than MI-MK2-/-mice. MK2-deficiency did not affect the increase in wall motion score index. Infiltration of neutrophils or monocytes did not differ significantly. Cytokine and chemokine transcripts were quantified in infarcted and non-infarcted LV tissue using qPCR arrays (QIAGEN). Three days post-MI,Ifna2was increased andIl16was decreased in infarcted tissue from MK2-/-hearts, compared with infarcted MK2+/+tissue, whereas in the non-infarcted MK2-/-myocardiumIl27increased andTnfsf11,Ccl3, andIl1rnwere decreased. Five days post-MI,Ctf16andIl10increased in infarcted MK2-/-tissue whereas in the non-infarcted MK2-/-myocardiumCcl9, Nodal, and Xcl2increased andIl15decreased.Conclusions:The findings of this study suggest MK2-deficiency is an advantage during the inflammatory phase of cardiac wound repair post-MI.Clinical PerspectiveWhat is new?-The effects of MAP kinase-activated protein kinase 2 (MK2) deficiency on survival, cardiac structure and function, and the inflammatory phase of wound healing following myocardial infarction were assessed using a constitutive, pan MK2-null mouse model.-MK2-deficiency reduced mortality but did not alter area at risk or infarct size post-myocardial infarction. Inflammatory cell infiltration was also unaffected.-MK2-deficiency altered the abundance of several cytokines (increased, decreased) in infarcted and non-infarcted myocardium post-MI.What are the clinical implications?-The initial phase of wound repair post-MI involves inflammation.-The risk of damage to the myocardium and mortality may be reduced by inhibition of MK2 activity during the inflammatory phase of wound healing post-MI.