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

Trepanier, J.; Nawaito, S. A.; Sahadevan, P.; Sahmi, F.; Duquette, N.; Gelinas, D.; Gillis, M.-A.; Shi, Y.; Torok, C.; Clavet-Lanthier, M.-E.; Gaestel, M.; Sirois, M. G.; Tardif, J.-C.; Allen, B. G.

doi:10.1101/2023.03.06.531384

bioRxiv · 10.1101/2023.03.06.531384

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

Trepanier, J.·Nawaito, S. A.·Sahadevan, P.·Sahmi, F.·Duquette, N.·Gelinas, D.·Gillis, M.-A.·Shi, Y.·Torok, C.·Clavet-Lanthier, M.-E.·Gaestel, M.·Sirois, M. G.·Tardif, J.-C.·Allen, B. G.

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Abstract

BackgroundAltering the onset, intensity, or duration of inflammation can impact the recovering hearts 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 ResultsMyocardial 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, Ifna2 was increased and Il16 was decreased in infarcted tissue from MK2-/- hearts, compared with infarcted MK2+/+ tissue, whereas in the non-infarcted MK2-/- myocardium Il27 increased and Tnfsf11, Ccl3, and Il1rn were decreased. Five days post-MI, Ctf16 and Il10 increased in infarcted MK2-/- tissue whereas in the non-infarcted MK2-/- myocardium Ccl9, Nodal, and Xcl2 increased and Il15 decreased. ConclusionsThe 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.

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Trepanier, J., Nawaito, S. A., Sahadevan, P., Sahmi, F., Duquette, N., Gelinas, D., Gillis, M.-A., Shi, Y., Torok, C., Clavet-Lanthier, M.-E., Gaestel, M., Sirois, M. G., Tardif, J.-C., Allen, B. G.. 2023-03-08. MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice. https://doi.org/10.1101/2023.03.06.531384

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