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

To observe the ameliorative effect of inhibiting acetyl-CoA carboxylase 2(ACC2) on cardiac dysfunction in septic mice and investigate its underlying mechanism.

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 (ACC2^ΔCM) mice were constructed by Cre-LoxP recombinase system, and ACC2^flox/flox Myh6-Cre^-(ACC2^fl/fl) mice were used as control.Several genetically engineered mice (8 weeks old, 20~25 g, male) were divided into ACC2^fl/fl+sham operation group, ACC2^fl/fl+sepsis group, ACC2^ΔCM+sepsis group, ACC2^ΔCM+Mal-CoA+sepsis group, and ACC2^ΔCM+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.

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 ACC2^fl/fl+sham operation group, the ACC2^ΔCM+sepsis group showed significant improvement in myocardial contraction compared with the ACC2^fl/fl+sepsis group, with the contraction amplitude of cardiomyocytes recovered by 48.1%, and significantly restored calcium sensitivity (P < 0.05).ACC2^ΔCM+Mal-CoA+sepsis group showed a notable decrease in myocardial cell contraction amplitude and a significant decrease in calcium sensitivity when compared to the ACC2^ΔCM+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 ACC2^ΔCM+sepsis group mice was lower than that of sepsis group (P < 0.05).The 36-hour survival rate of the ACC2^ΔCM+sepsis group.mice was 37.5% higher than that of the ACC2^fl/fl+sepsis group mice.(P < 0.05).

Inhibition of ACC2 exerts a protective effect on myocardial contractility and calcium sensitivity in septic mice by reducing Mal-CoA.