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

Activation of Ventrolateral Part of Ventromedial Hypothalamus Aggravates Cardiac Function after Myocardial Infarction

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(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。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,激活成动转染病毒的VMHVL神经元。14 d后,检测心脏二维超声心动图,取静脉血检测血清去甲肾上腺素浓度,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]。检测静脉血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,VMHVL激活可显著恶化心肌梗死后的心室重塑,左室直径和容积进一步扩大[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:(1.28±0.21)mL vs(0.65±0.15)mL,P<0.0001],心脏功能进一步降低[左室射血分数:(63.60±2.12)%vs(44.90±6.39)%,P<0.005;左室短轴缩短率:(29.39±3.36)%vs(19.62±3.27)%,P<0.01]。结论化学遗传激活VMHVL可进一步恶化心肌梗死后心脏结构改变和功能下降。

Objective We aimed to chemogenetically activate emotion-related nuclei in the ventrolateral part of ventromedial 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 brain stereotactic technology,and the control group was microinjected with the same dose of rAAV-hSyn-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 establish a myocardial infarction model,following an intraperitoneal injection of Clozapine N-oxide(CNO,3.3 mg/kg)for 14 days to activate VMHVL neurons.After 14 days,we measured two-dimensional echocardiography of the heart,collected venous blood for norepinephrine(NE)detecting and VMHVL brain frozen slices for immunofluorescence staining.Results Comparing with the control group,VMHVL neurons in the activation group were significantly activated by CNO[normalized C-FOS positive cells count:(1.40±0.08)vs(1.00±0.09),P<0.01],and serum NE was significantly increased in the activated group[(4372.26±221.10)pg/mL vs(2018.47±466.89)pg/mL,P<0.001].Cardiac structure remodeling was aggravated[LVIDs:(6.74±0.50)mm vs(4.38±0.48)mm,P<0.005;LVIDd:(8.36±0.55)mm vs(6.54±0.54)mm,P<0.01;LVESV:(0.70±0.15)mL vs(0.22±0.08)mL,P<0.001;LVEDV:(1.28±0.21)mL vs(0.65±0.15)mL,P<0.0001],and cardiac function was decreased[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.