Exercise Preconditioning Protects against Acute Cardiac Injury Induced by Lipopolysaccharide Through General Control Nonderepressible 2 Kinase

Abstract

Exercise preconditioning may protect against cardiac injury induced by lipopolysaccharide (LPS), but the mechanism is unresolved. The aim of this study is to explore whether the general control nonderepressible 2 (GCN2) kinase gene is associated with the protective effect of exercise preconditioning. Eight-week-old male C57BL/6J (n = 40) and GCN2 knockout (KO) (n = 40) mice were divided into four groups: control, LPS (L), exercise preconditioning (E), and exercise preconditioning LPS (EL). Mice in the exercise groups performed exercise for eight weeks. After exercise, all mice were given an equal volume of LPS or saline (10 μg/g). We measured the cardiac function using echocardiography and then collected heart tissue. Exercise preconditioning improved cardiac inflammation (interleukin-6, tumor necrosis factor α) and cardiac dysfunction (ejection fraction, fraction shortening) in C57 mice induced by LPS and also decreased the expression levels of GCN2, phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 (ATF4). Moreover, GCN2 KO decreased inflammation and cardiac dysfunction induced by LPS in sedentary mice. The inflammation and cardiac dysfunction in the GCN2 KO EL group were lower than in the C57 EL group, and the expression of GCN2, p-eIF2α, and ATF4 in the GCN2 KO EL group was lower than in the C57 EL group. 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, and the GCN2 and eIF2α/ATF4 pathways play an important role in the process.