Exercise Preconditioning Alleviate LPS Induced Acute Heart Injury Through GCN2 Pathway

Abstract

Exercise preconditioning may protect against cardiac injury induced by lipopolysaccharide (LPS), but the mechanism is unresolved. PURPOSE: This study aims to explore whether the general control nonderepressible 2 kinase (GCN2) gene is associated with the protective effect of exercise preconditioning. METHODS: 8 weeks old male GCN2 knockout (KO, n = 40) and wild type control with C57BL/6J background (C57, n = 40) mice were respectively divided into 4 groups: control, LPS (L), exercise preconditioning (E) and exercise preconditioning LPS (EL). Mice in the exercise groups performed exercise for 8 weeks. After exercise, all mice were administered an equal volume of LPS (10 μg/g body weight) or saline. Heart function were measured by Vevo1100 small animal echocardiography 6 hours later followed by immediately tissue collection for Western blots and histological analysis. RESULTS: Exercise preconditioning was observed to improve cardiac dysfunction evaluated by ejection fraction (EF) value (C57 L: 50.34 ± 6.94 vs. C57 EL: 59.32 ± 3.63, p<0.05) and also significantly decreased the expression levels of GCN2, phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) and activating transcription factor 4 (ATF4) in C57 mice induced by LPS (p<0.05). Moreover, GCN2 KO decreased cardiac dysfunction induced by LPS in sedentary mice. The cardiac dysfunction in the GCN2 KO EL group were lower than that in C57 EL group, and the expression of GCN2, p-eIF2α and ATF4 in the GCN2 KO EL group was significantly lower than that in C57 EL group (p<0.05). CONCLUSION: Exercise preconditioning alleviated cardiac injury induced by LPS. GCN2 KO also improved cardiac injury. Exercise preconditioning promoted the effect of GCN2 KO in alleviating cardiac injury, GCN2 and eIF2α/ATF4 pathway play an important role in the process.