抑制乙酰辅酶A羧化酶2改善脓毒症小鼠心功能障碍的机制研究

杜云霞; 佘汉; 吴银雨; 王易; 周远群; 王维飞; 李涛; 胡弋; 毛庆祥

doi:10.16016/j.2097-0927.202406038

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抑制乙酰辅酶A羧化酶2改善脓毒症小鼠心功能障碍的机制研究

基础医学 | 更新时间：2026-01-09

- 抑制乙酰辅酶A羧化酶2改善脓毒症小鼠心功能障碍的机制研究
- Mechanism of inhibiting acetyl CoA carboxylase 2 to improve cardiac dysfunction in septic mice
- 陆军军医大学学报 2024年46卷第24期页码：2689-2697
- 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：
  
  [毛庆祥，E-mail: qxmao@tmmu.edu.cnMAO Qingxiang, E-mail: qxmao@tmmu.edu.cn
- 基金信息：
  
  ‍国家自然科学基金青年科学项目(82300561);重庆英才创新领军人才项目(CSTC2024YCJH-BGZXM0011);重庆市自然科学基金面上项目(CSTB2023NSCQ-MSX0713)
- DOI：10.16016/j.2097-0927.202406038
  中图分类号： R322.11;R631.1;R977.3
- 收稿：2024-06-14，
  
  修回：2024-10-22，
  
  纸质出版：2024-12-30
- 稿件说明：
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杜云霞, 佘汉, 吴银雨, 等. 抑制乙酰辅酶A羧化酶2改善脓毒症小鼠心功能障碍的机制研究[J]. 陆军军医大学学报, 2024,46(24):2689-2697.

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.
杜云霞, 佘汉, 吴银雨, 等. 抑制乙酰辅酶A羧化酶2改善脓毒症小鼠心功能障碍的机制研究[J]. 陆军军医大学学报, 2024,46(24):2689-2697. DOI： 10.16016/j.2097-0927.202406038.

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

SINGER M, DEUTSCHMAN C S, SEYMOUR C W, et al . The third international consensus definitions for sepsis and septic shock (sepsis-3)[J ] . JAMA, 2016, 315(8): 801-810. DOI: 10.1001/jama.2016.0287.

Rudd K E, Johnson S C, Agesa K M, et al . Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study[J ] . Lancet, 2020, 395: 200-211. DOI: 10.1016/s0140-6736(19)32989-7

XIE J F, WANG H L, KANG Y, et al . The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey[J ] . Crit Care Med, 2020, 48(3): e209-e218. DOI: 10.1097/CCM.0000000000004155.

HOLLENBERG S M, SINGER M. Pathophysiology of sepsis-induced cardiomyopathy[J]. Nat Rev Cardiol, 2021, 18(6): 424-434. DOI: 10.1038/s41569-020-00492-2.

MARTIN L, DERWALL M, AL ZOUBI S, et al . The septic heart: current understanding of molecular mechanisms and clinical implications[J ] . Chest, 2019, 155(2): 427-437. DOI: 10.1016/j.chest.2018.08.1037.

TAN L, SHE H, ZHENG J, et al . Effects of Malate Ringer's solution on myocardial injury in sepsis and enforcement effects of TPP@PAMAM-MR[J ] . J Transl Med, 2022, 20(1): 591. DOI: 10.1186/s12967-022-03811-y.

SHE H, HU Y, ZHOU Y Q, et al . Protective effects of dexmedetomidine on sepsis-induced vascular leakage by alleviating ferroptosis via regulating metabolic reprogramming[J ] . J Inflamm Res, 2021, 14: 6765-6782. DOI: 10.2147/JIR.S340420..

SHE H, TAN L, DU Y L, et al . VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis[J ] . Int J Biol Sci, 2023, 19(10): 3143-3158. DOI: 10.7150/ijbs.84613..

DE BACKER D, SCOLLETTA S. Clinical management of the cardiovascular failure in sepsis[J]. Curr Vasc Pharmacol, 2013, 11(2): 222-242.

WANG Y, YU W X, LI S, et al . Acetyl-CoA carboxylases and diseases[J ] . Front Oncol, 2022, 12: 836058. DOI: 10.3389/fonc.2022.836058.

CHEN J Q, ZOU L, LU G, et al . PFKP alleviates glucose starvation-induced metabolic stress in lung cancer cells via AMPK-ACC2 dependent fatty acid oxidation[J ] . Cell Discov, 2022, 8(1): 52. DOI: 10.1038/s41421-022-00406-1..

FULLERTON M D, GALIC S, MARCINKO K, et al . Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin[J ] . Nat Med, 2013, 19(12): 1649-1654. DOI: 10.1038/nm.3372.

SHAO D, KOLWICZ S C Jr, WANG P, et al . Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating parkin-mediated mitophagy[J ] . Circulation, 2020, 142(10): 983-997. DOI: 10.1161/CIRCULATIONAHA.119.043319.

张濒丹, 张杰, 孙悦, 等. 丙泊酚对脓毒症心肌收缩功能障碍的改善作用及机制[J]. 陆军军医大学学报, 2023, 45(22): 2310-2318. DOI: 10.16016/j.2097-0927.202303171.

ZHANG B D, ZHANG J, SUN Y, et al . Effect and mechanism of propofol on myocardial contractile dysfunction in sepsis[J ] . J Army Med Univ, 2023, 45(22): 2310-2318. DOI: 10.16016/j.2097-0927.202303171.

THUPARI J N, PINN M L, KUHAJDA F P. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity[J]. Biochem Biophys Res Commun, 2001, 285(2): 217-223. DOI: 10.1006/bbrc.2001.5146.

GORSKI P A, KHO C, OH J G. Measuring cardiomyocyte contractility and calcium handling in vitro [J ] . Methods Mol Biol, 2018, 1816: 93-104. DOI: 10.1007/978-1-4939-8597-5_7.

HOBAI I A, EDGECOMB J, LABARGE K, et al . Dysregulation of intracellular calcium transporters in animal models of sepsis-induced cardiomyopathy[J ] . Shock, 2015, 43: 3-15. DOI:10.1097/shk.0000000000000261.

JOZEFOWICZ E, BRISSON H, ROZENBERG S, et al . Activation of peroxisome proliferator-activated receptor-alpha by fenofibrate prevents myocardial dysfunction during endotoxemia in rats[J ] . Crit Care Med, 2007, 35: 856-863. DOI:10.1097/01.Ccm.0000256843.75446.A0

KANG Z Q, ZHANG Z, LI J, et al . Mechanistic of AMPK/ACC2 regulating myoblast differentiation by fatty acid oxidation of goat[J ] . Int J Biol Macromol, 2024, 270(Pt 2): 132243. DOI: 10.1016/j.ijbiomac.2024.132243.

O'NEILL H M, LALLY J S, GALIC S, et al . Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise[J ] . Physiol Rep, 2015, 3(7): e12444. DOI: 10.14814/phy2.12444.

ROSS T T, CROWLEY C, KELLY K L, et al . Acetyl-CoA carboxylase inhibition improves multiple dimensions of NASH pathogenesis in model systems[J ] . Cell Mol Gastroenterol Hepatol, 2020, 10: 829-851. DOI:10.1016/j.jcmgh.2020.06.001

YOON H, SPINELLI J B, ZAGANJOR E, et al . PHD3 loss promotes exercise capacity and fat oxidation in skeletal muscle[J ] . Cell Metab, 2020, 32(2): 215-228. e7. DOI: 10.1016/j.cmet.2020.06.017.

ABU-ELHEIGA L, MATZUK M M,ABO-HASHEMA K A, et al . Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2[J ] . Science, 2001, 291(5513): 2613-2616. DOI: 10.1126/science.1056843.

CHOI Y S, DE MATTOS A B M, SHAO D, et al . Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin Ⅱ infusion[J ] . J Mol Cell Cardiol, 2016, 100: 64-71. DOI: 10.1016/j.yjmcc.2016.09.001.

GALVAN-PENA S, CARROLL R G, NEWMAN C, et al . Malonylation of GAPDH is an inflammatory signal in macrophages[J ] . Nat Commun, 2019, 10(1): 338. DOI: 10.1038/s41467-018-08187-6.

HARRIMAN G, GREENWOOD J, BHAT S, et al . Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats[J ] . Proc Natl Acad Sci USA, 2016, 113(13): E1796-E1805. DOI: 10.1073/pnas.1520686113.

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