Mechanism of inhibiting acetyl CoA carboxylase 2 to improve cardiac dysfunction in septic mice

Objective To observe the ameliorative effect of inhibiting acetyl-CoA carboxylase 2(ACC2) on cardiac dysfunction in septic mice and investigate its underlying mechanism. Methods Mouse model of sepsis was established by cecal ligation and perforation.A total of 24 male C57BL/6 mice (aged 8 weeks, weighing 20~25 g) were divided into sham operation group, sepsis group and ND-630+sepsis group.The cardiac specific ACC2 knockout (ACC2ΔCM) mice were constructed by Cre-LoxP recombinase system, and ACC2flox/flox Myh6-Cre-(ACC2fl/fl) mice were used as control.Several genetically engineered mice (8 weeks old, 20~25 g, male) were divided into ACC2fl/fl+sham operation group, ACC2fl/fl+sepsis group, ACC2ΔCM+sepsis group, ACC2ΔCM+Mal-CoA+sepsis group, and ACC2ΔCM+sham operation group according to the random number table method.The contractile function and myofilament calcium sensitivity of cardiomyocytes were measured by a cell microtensiometer.Western blotting was used to detect the expression level of ACC2, and ELISA was employed to measure the level of malonyl-CoA (Mal-CoA) in myocardial tissue.The survival of the mice in 36 h after sepsis was observed. Results Compared with the sham operation group, the contraction amplitude of cardiomyocytes in sepsis group was decreased markedly, and the calcium sensitivity decreased significantly as well (P < 0.05).Based on the ACC2fl/fl+sham operation group, the ACC2ΔCM+sepsis group showed significant improvement in myocardial contraction compared with the ACC2fl/fl+sepsis group, with the contraction amplitude of cardiomyocytes recovered by 48.1%, and significantly restored calcium sensitivity (P < 0.05).ACC2ΔCM+Mal-CoA+sepsis group showed a notable decrease in myocardial cell contraction amplitude and a significant decrease in calcium sensitivity when compared to the ACC2ΔCM+sepsis group (P < 0.05).Compared with the sepsis group, the contraction amplitude of cardiomyocytes in the ND-630+sepsis group increased significantly, and the calcium sensitivity of myofilament also increased (P < 0.05).The expression level of ACC2 protein in the myocardial tissue of mice in the sepsis group increased compared to the sham operation group (P < 0.05).The level of myocardial Mal-CoA in the sepsis group was higher than that in the sham operation group (P < 0.05);Mal-CoA level in the myocardium of ACC2ΔCM+sepsis group mice was lower than that of sepsis group (P < 0.05).The 36-hour survival rate of the ACC2ΔCM+sepsis group.mice was 37.5% higher than that of the ACC2fl/fl+sepsis group mice.(P < 0.05). Conclusion Inhibition of ACC2 exerts a protective effect on myocardial contractility and calcium sensitivity in septic mice by reducing Mal-CoA.