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

Yunxia DU; Han SHE; Yinyu WU; Yi WANG; Yuanqun ZHOU; Weifei WANG; Tao LI; Yi HU; Qingxiang MAO

doi:10.16016/j.2097-0927.202406038

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

Basic Medicine | 更新时间：2026-01-09

- Mechanism of inhibiting acetyl CoA carboxylase 2 to improve cardiac dysfunction in septic mice
- Journal of Army Medical University Vol. 46, Issue 24, Pages: 2689-2697(2024)
- 作者机构：
  
  1.400042 重庆，陆军特色医学中心麻醉科
  2.400042 重庆，陆军特色医学中心野战外科研究部战伤休克与输血研究室
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(82300561);the Innovative Leading Talents of Chongqing Talent Program(CSTC2024YCJH-BGZXM0011);the General Project of Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0713)
- DOI：10.16016/j.2097-0927.202406038
  CLC： R322.11;R631.1;R977.3
- Received：14 June 2024，
  
  Revised：2024-10-22，
  
  Published：30 December 2024
- 稿件说明：
移动端阅览
Yunxia DU, Han SHE, Yinyu WU, et al. Mechanism of inhibiting acetyl CoA carboxylase 2 to improve cardiac dysfunction in septic mice[J]. Journal of Army Medical University, 2024, 46(24): 2689-2697.
DOI：

Yunxia DU, Han SHE, Yinyu WU, et al. Mechanism of inhibiting acetyl CoA carboxylase 2 to improve cardiac dysfunction in septic mice[J]. Journal of Army Medical University, 2024, 46(24): 2689-2697. DOI： 10.16016/j.2097-0927.202406038.

摘要

目的

观察抑制乙酰辅酶A羧化酶2(acetyl-CoA carboxylase 2

ACC2)对脓毒症小鼠心脏功能障碍的改善作用并研究其机制。

方法

采用盲肠结扎穿孔术建立小鼠脓毒症模型

取24只8周龄且体质量为20~25 g的雄性C57BL/6小鼠

按照随机数字表法分为假手术组、脓毒症组、ND-630+脓毒症组。利用Cre-LoxP重组酶系统构建心脏特异性ACC2敲除小鼠(ACC2

ΔCM

)

并以ACC2

flox

Myh6-Cre

(ACC2

)小鼠作为对照

取48只ACC2

小鼠、48只ACC2

ΔCM

小鼠(8周龄

20~25 g

雄性)按照随机数字表法分为ACC2

+假手术组、ACC2

+脓毒症组、ACC2

ΔCM

+脓毒症组、ACC2

ΔCM

+Mal-CoA+脓毒症组、ACC2

ΔCM

+假手术组。采用细胞微张力仪检测心肌细胞收缩功能与肌丝钙敏感性; Western blot检测ACC2蛋白表达水平; ELISA检测心肌组织中丙二酰辅酶A (malonyl-CoA

Mal-CoA)水平。观察小鼠脓毒症后36 h存活情况。

结果

脓毒症组较假手术组心肌细胞收缩幅度显著下降

钙敏感性显著下降(

0.05);以ACC2

+假手术组为基础水平

ACC2

ΔCM

+脓毒症组较ACC2

+脓毒症组心肌细胞收缩幅度恢复48.1%

钙敏感性明显恢复(

05);ACC2

ΔCM

+Mal-CoA+脓毒症组较ACC2

ΔCM

+脓毒症组心肌细胞收缩幅度与钙敏感性明显下降(

0.05);ND-630+脓毒症组较脓毒症组心肌细胞收缩幅度与肌丝钙敏感性上升(

0.05)。脓毒症组较假手术组小鼠心肌组织ACC2蛋白表达水平增加(

0.05)。脓毒症组心肌Mal-CoA水平较假手术组升高(

0.05);ACC2

ΔCM

+脓毒症组小鼠心肌Mal-CoA水平较脓毒症组降低(

0.05)。ACC2

ΔCM

+脓毒症组较ACC2

+脓毒症组36 h存活率提高37.5%(

0.05)。

结论

抑制ACC2通过降低Mal-CoA水平对脓毒症小鼠心肌收缩功能和钙敏感性发挥保护作用。

Abstract

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 (ACC2

ΔCM

) mice were constructed by Cre-LoxP recombinase system

and ACC2

flox

Myh6-Cre

(ACC2

) mice were used as control.Several genetically engineered mice (8 weeks old

20~25 g

male) were divided into ACC2

+sham operation group

ACC2

+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.

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 (

0.05).Based on the ACC2

+sham operation group

the ACC2

ΔCM

+sepsis group showed significant improvement in myocardial contraction compared with the ACC2

+sepsis group

with the contraction amplitude of cardiomyocytes recovered by 48.1%

and significantly restored calcium sensitivity (

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 (

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 (

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 (

0.05).The level of myocardial Mal-CoA in the sepsis group was higher than that in the sham operation group (

0.05);Mal-CoA level in the myocardium of ACC2

ΔCM

+sepsis group mice was lower than that of sepsis group (

0.05).The 36-hour survival rate of the ACC2

ΔCM

+sepsis group.mice was 37.5% higher than that of the ACC2

+sepsis group

mice.(

0.05).

Conclusion

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

关键词

Keywords

references

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