[1]刘子韩 刘志豪 周雨扬 许骁 李泽衍 周丽平 江洪.下丘脑腹内侧核腹外侧区激活恶化心肌梗死后的心脏功能[J].心血管病学进展,2021,(4):380-384.[doi:10.16806/j.cnki.issn.1004-3934.2021.04.021]
　LIU Zihan,LIU Zhihao,ZHOU Yuyang,et al.Effect of Chemogenetic Activation of VMHVL on Cardiac Structure and Function after Myocardial Infarction[J].Advances in Cardiovascular Diseases,2021,(4):380-384.[doi:10.16806/j.cnki.issn.1004-3934.2021.04.021]
点击复制

下丘脑腹内侧核腹外侧区激活恶化心肌梗死后的心脏功能()
分享到：

《心血管病学进展》[ISSN:51-1187/R/CN:1004-3934]

卷:
期数:
2021年4期
页码:
380-384
栏目:
论著
出版日期:
2021-04-25

文章信息/Info

Title:
Effect of Chemogenetic Activation of VMHVL on Cardiac Structure and Function after Myocardial Infarction
作者:
刘子韩 刘志豪 周雨扬 许骁 李泽衍 周丽平 江洪
(武汉大学人民医院心内科 武汉大学心血管病研究所 心血管病湖北省重点实验室,湖北 武汉 430060)
Author(s):
LIU Zihan; LIU Zhihao; ZHOU Yuyang; XU Xiao; LI Zeyan; ZHOU Liping; JIANG Hong
(Department of Cardiology, Renmin Hospital of Wuhan University；Cardiovascular Research institute of Wuhan University；Hubei Key Laboratory of Cardiology，Wuhan 430060，Hube，iChina )
关键词:
化学遗传学; 下丘脑腹内侧核腹外侧区; 情绪应激; 心肌梗死; 心肌重构
Keywords:
Chemogenetic; VMHVL; Emotion stress; Myocardial infarction; Myocardial remodeling
DOI:
10.16806/j.cnki.issn.1004-3934.2021.04.021
摘要:
目的 化学遗传精准激活愤怒情绪相关核团下丘脑腹内侧核腹外侧区（ventrolateral part of ventromedial hypothalamus, VMHVL），探究其对大鼠心肌梗死后心脏功能的影响。方法 10只健康成年SD大鼠随机分为激活组（n＝5）和对照组（n＝5）。通过脑立体定位技术向激活组大鼠大脑右侧VMHVL微量注射rAAV-hSyn-hM3D (Gq)-EGFP-WPRE-pA，在对照组相同的脑区注射等量的rAAV-hSyn-EGFP-WPRE-pA，hM3D (Gq)受体可表达在神经元细胞膜上。注射病毒3周后，两组大鼠均开胸进行心脏左前降支结扎术构建心肌梗死模型，连续14 d腹腔注射氯氮平一氧化氮3.3 mg/kg，激活hM3D (Gq)受体以激活VMHVL神经元。14 d后，测量心脏二维超声心动图，取VMHVL脑冰冻切片作免疫荧光染色。结果 氯氮平一氧化氮注射14 d后，激活组的VMHVL神经元与对照组相比被显著激活[标准化C-FOS阳性细胞计数：（1.40±0.08）vs（1.00±0.09），P＜0.01]。检测外周血清发现激活组去甲肾上腺素水平显著升高[（4372.26±221.10）pg/mL vs（2018.47±466.89）pg/mL，P＜0.001]。超声结果显示，化学遗传激活VMHVL神经元可显著恶化心肌梗死后心室结构进一步重构，左心室直径和容积增大[左室收缩末期内径：（6.74±0.50）mm vs（4.38±0.48）mm，P＜0.005；左室舒张末期内径：（8.36±0.55）mm vs（6.54±0.54）mm，P＜0.01；左室收缩末期容积：（0.70±0.15）mL vs （ 0.22±0.08）mL，P＜0.001；左室舒张末期容积：（1.276±0.21）mL vs（0.65±0.15）mL，P＜0.000 1]，心脏功能进一步降低[左室射血分数：(63.6±2.12）% vs（44.9±6.39）%，P＜0.005；左室短轴缩窄率：（29.39±3.36）% vs（19.62±3.27）%，P＜0.01]。结论 化学遗传激活VMHVL可显著恶化心肌梗死后心脏结构改变和功能下降。
Abstract:
Obiective We aimed to chemogenetically activate emotion-related nuclei in the yentrolateral part of yentromedial hypothalamus(VMHVL),and explore its effect on cardiac function in rats after myocardial infarction.Methods 10 healthy adult SD rats were randomly divided into activation group(n=5)and control group(n=5).The rAAV-hSyn-hM3D(Gq)-EGFP-WPRE-pA was microinjected into the right VMHVL. by hrain stereotuctic technology,and the control group was microinjected with the same dose of rAAV-ISyn-EGFP-WPRE-pA in the right VMHVL. After three weeks,both of two groups underwent thoracotomy for ligation of the left anterior descending artery of the heart to estahlish a myocardial infarction model,following an intraperitoneal injection of Clozapine N-oxid(CNO,3.3 mg/kg)for 14 days to activate VMHVL neurons. After 14 days,we measured two-dimensional echocardography of the heart,collected venous hood for norepinephrine(NE) detecting and VMHVL brain frozen slices for immunofluorescence staining.Results Comparing with the conml groun.VMHVIneurons in the activation group were significanly activated by CNO[normalized C-FOS positive cells count-(1.40±0.08) y(1.00±0. 0).Pe0.01 ] and serum NE was significantly inemased in the activated group[[(4 372.26±221.10)pg/mL vs(2 018.47±466.89)pg/mL,P<0.001].Cardiac strudure remodeling was agravated[LVIDs:(6.74±0.50)mm vs (4.38±0.48)nm,P<0.005;LVIDd:(8.36±0.55)mm ws(6.54±0.54)mm,P0.01;LVESV;(0.70±0.15)mLw(0.22±0.08)mL,P<0.001;LVEDV;(1.28±0.21)mL w(0.65±0.15)mL.P<0.000 11.and cardiac function was deereasd[LVEF;(63.60±2.12)% vs(44.90±6.39)%,P<0.005;LVFS:(29.39±3.36)% vs(19.62±3.27)%, P<0.01].Conclusion Chemogenetic activation of VMHVL can significantly aggravate the cardiac dysfunction and structure alteration after myocardial infarction. farction.

参考文献/References:

[1]Arnett DK,Blumenthal RS,Albert MA,et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease:A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[J]. Circulation,2019,140(11):e649-e650.

[2]Nabi H,Kivim?ki M,Batty GD,et al. Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health:the Whitehall II prospective cohort study[J]. Eur Heart J,2013,34(34):2697‐2705.

[3]Redwine LS,Wirtz PH,Hong S,et al. Depression as a potential modulator of Beta-adrenergic-associated leukocyte mobilization in heart failure patients[J]. J Am Coll Cardiol, 2010 ,56(21):1720-1727.

[4]Blumenthal JA,Sherwood A,Smith PJ,et al. Enhancing Cardiac Rehabilitation With Stress Management Training:A Randomized,Clinical Efficacy Trial[J]. Circulation,2016,133(14):1341-1350.

[5]邵枫,林文娟,王玮雯,等. 情绪应激对不同脑区c-fos表达的影响[J].心理学报,2003(05):685-689.

[6]Nakamura Y,Nakamura K. Central regulation of brown adipose tissue thermogenesis and energy homeostasis dependent on food availability[J]. Pflugers Arch,2018,470(5):823‐837.

[7]Contreras C,González-García I,Martínez-Sánchez N,et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance[J]. Cell Rep,2014,9(1):366‐377.

[8]Remedios R,Kennedy A,Zelikowsky M,et al. Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex[J]. Nature,2017,550(7676):388‐392.

[9]Lin D,Boyle MP,Dollar P,et al. Functional identification of an aggression locus in the mouse hypothalamus[J]. Nature,2011,470(7333):221-226.

[10]Pessoa L. A network model of the emotional brain[J]. Trends Cogn Sci,2017,21(5):357-371.

[11]Goldfarb EV,Rosenberg MD,Seo D,et al. Hippocampal seed connectome-based modeling predicts the feeling of stress [J]. Nat Commun,2020,11(1):2650.

[12]Ulrich-Lai YM,Herman JP. Neural regulation of endocrine and autonomic stress responses[J]. Nat Rev Neurosci,2009,10(6):397-409.

[13]Sweeney P,Yang Y. Neural Circuit Mechanisms Underlying Emotional Regulation of Homeostatic Feeding[J]. Trends Endocrinol Metab,2017,28(6):437-448.

[14]Kataoka N,Shima Y,Nakajima K,et al. A central master driver of psychosocial stress responses in the rat [J]. Science,2020,367(6482):1105-1112.

[15]James C,Macefield VG,Henderson LA. Real-time imaging of cortical and subcortical control of muscle sympathetic nerve activity in awake human subjects[J]. Neuroimage,2013,70:59-65.

[16]Ulrich-Lai YM,Herman JP. Neural regulation of endocrine and autonomic stress responses[J]. Nat Rev Neurosci,2009,10(6):397-409.

[17]Roth BL. DREADDs for neuroscientists[J]. Neuron,2016,89(4):683-694.

[18]Armbruster BN,Li X,Pausch MH,et al. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand[J]. Proc Natl Acad Sci U S A,2007,104(12):5163-5168.

[19]Alexander GM,Rogan SC,Abbas AI,et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors [J]. Neuron,2009,63(1):27-39.

[20]Krashes MJ,Koda S,Ye C,et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice[J]. J Clin Invest,2011,121(4):1424-1428.

[21]Steculorum SM,Ruud J,Karakasilioti I,et al. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue [J]. Cell,2016,165(1):125-138.

[22]Burnett CJ,Krashes MJ. Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs[J]. J Neurosci,2016,36(36):9268-9282.

[23]Guettier JM,Gautam D,Scarselli M,et al. A chemical-genetic approach to study G protein regulation of beta cell function in vivo[J]. Proc Natl Acad Sci U S A,2009,106(45):19197-19202.

[24]Puddu PE,Jouve R,Langlet F,et al. Prevention of postischemic ventricular fibrillation late after right or left stellate ganglionectomy in dogs [J]. Circulation,1988,77(4):935‐946.

[25]Infanger DW,Cao X,Butler SD,et al. Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis[J]. Circ Res,2010,106(11):1763‐1774.

[26]Lo L,Yao S,Kim DW,et al. Connectional architecture of a mouse hypothalamic circuit node controlling social behavior[J]. Proc Natl Acad Sci U S A,2019,116(15):7503‐7512.

备注/Memo

备注/Memo:
基金项目： 国家重点研发计划(2017YFC1307802)；国家自然科学基金( 81970287 ， 81530011)
通信作者： 江洪，E-mail： Hongj0505@126.com
收稿日期 ： 2020-10-28
更新日期/Last Update: 2021-07-01