Macrophage migration inhibitory factor knockout attenuates endotoxin-induced cardiac dysfunction in mice

Accumulated evidence suggests that macrophage migration inhibitory factor (MIF) plays a key role not only in acute and chronic inflammatory diseases but also in cardiovascular disease. The cardiac dysfunction is related to lipopolysac-charide (LPS) in sepsis.

This study was designed to examine whether MIF mediates LPS-induced cardiac dysfunction and address the mechanisms.

Echocardiography, immunohistochemical analysis, cell shortening/re-lengthening, and intracellular Ca2+ fluores-cence evaluation were performed in whole hearts and isolated cardiomyocytes from C57 and MIF knockout mice treated with or without LPS. Reactive oxygen species and protein carbonyl formation were measured. Activation of mitogen-activated protein kinases and endoplasmic reticulum stress markers were evaluated using Western blot analysis. Human umbilical vein endothelial cells (HUVECs) were transfected with lentiviruses carrying short hairpin RNA (shRNA) to inhibit MIF.

Echocardiography revealed that cardiac function was impaired and macrophage infiltration was increased in LPS-treated C57 mice. Peak shortening and maximal velocity of shortening/re-lengthening were significantly reduced and the duration of re-lengthening was prolonged in LPS-treated C57 mice. Reactive oxygen species and protein carbonyl levels were increased in LPS-treated C57 mice. These dysfunctional changes were attenuated in MIF knockout mice that were challenged with LPS. Western blot analysis revealed that activated p-JNK, p-ERK, and endoplasmic reticulum stress protein marker expression was decreased in LPS-treated MIF knockout mice. p-ERK and p-JNK levels were knocked down in MIF shRNA-transfected HUVECs.

The data collectively suggest that MIF mediates LPS-induced cardiac dysfunction in murine cardiomyocytes, which was attenuated by MIF knockout, and the therapeutic option with regard to MIF may aid the management of cardiac dysfunction in sepsis.