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小鼠对异丙肾上腺素处理的品系特异性反应

李双玲^1,2, 王顺^1,2, 何元^1,2, 郑迪^1,2, 吕舰^1,2, 郭宁宁^1,2, 郭莹莹^1,2, 李丽莉^1,2, 范明霞³, 王志华^1,3,*

¹武汉大学人民医院心内科，武汉 430060；²武汉大学人民医院中心实验室，武汉 430060；³武汉大学人民医院实验动物中心，武汉 430060

摘要

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O2 consumption at state III with either complex I substrates or complex II substrate, compared with those from FVB/nJ mice. ISO treatment did not affect mitochondrial respiratory control rate (RCR), but significantly suppressed the ADP/O ratio generated from the complex II substrate in both strains. The ADP/O ratio generated from the complex I substrates in A/J mice declined by 50% after ISO treatment, whereas FVB/nJ mice were not affected. These results suggest that, compared with FVB/nJ mice, A/J mice possesses a poor integrity of mitochondrial respiratory chain that might contribute to its vulnerability to ISO-induced cardiac hypertrophy.

关键词： 小鼠品系; 心肌肥厚; 异丙肾上腺素; 线粒体; 氧化磷酸化; ADP/O比值

分类号：R541

Mouse strain-specific responses of mitochondrial respiratory function and cardiac hypertrophy to isoproterenol treatment

LI Shuang-Ling^1,2, WANG Shun^1,2, HE Yuan^1,2, ZHENG Di^1,2, LYU Jian^1,2, GUO Ning-Ning^1,2, GUO Ying-Ying^1,2, LI Li-Li^1,2, FAN Ming-Xia³, WANG Zhi-Hua^1,3,*

¹Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China；²Central Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China；³Animal Center, Renmin Hospital of Wuhan University, Wuhan 430060, China

Abstract

心肌肥厚是各种心血管疾病共同的病理过程，最终发展为心力衰竭。本文旨在研究不同品系小鼠在肥大刺激后表现出的不同病理学特征。通过动物微量注射泵泵入异丙肾上腺素(isoproterenol, ISO)诱导A/J和FVB/nJ小鼠心肌肥厚，用超声心动图监测心脏形态和功能。从各组小鼠心脏中分离线粒体，检测其氧化磷酸化功能。结果显示，两种品系小鼠在1周ISO处理后均表现出心脏收缩功能的代偿性增强。A/J小鼠(而非FVB/nJ小鼠)在3周ISO处理后出现明显的心肌肥厚，主要表现为左室后壁厚度、心重/体重比、心肌细胞横截面积和心肌肥大标志物表达均显著增加。与FVB/nJ小鼠相比，A/J小鼠心脏含有更高的线粒体DNA拷贝数；且无论是在复合物I底物还是复合物II底物中，A/J小鼠线粒体在state III时的耗氧速率都更高。ISO处理对两种品系小鼠心脏线粒体呼吸控制率没有显著影响，但显著抑制两种品系小鼠自复合物II底物产生的ADP/O比值。在ISO处理后，A/J小鼠线粒体自复合物I底物产生的ADP/O比值下降了约50%，而FVB/nJ小鼠不受影响。以上结果提示，相对于FVB/nJ小鼠，A/J小鼠线粒体呼吸链的完整性较差，这可能是其易受ISO诱导产生心肌肥厚的原因之一。

Key words: mouse strain; cardiac hypertrophy; isoproterenol; mitochondria; oxidative phosphorylation; ADP/O ratio

收稿日期：2020-08-17　　录用日期：2021-03-22

通讯作者：王志华　　E-mail: zhihuawang@whu.edu.cn

DOI: 10.13294/j.aps.2021.0041

引用本文：

李双玲, 王顺, 何元, 郑迪, 吕舰, 郭宁宁, 郭莹莹, 李丽莉, 范明霞, 王志华. 小鼠对异丙肾上腺素处理的品系特异性反应[J]. 生理学报 2021; 73 (3): 459-470.

LI Shuang-Ling, WANG Shun, HE Yuan, ZHENG Di, LYU Jian, GUO Ning-Ning, GUO Ying-Ying, LI Li-Li, FAN Ming-Xia, WANG Zhi-Hua. Mouse strain-specific responses of mitochondrial respiratory function and cardiac hypertrophy to isoproterenol treatment. Acta Physiol Sin 2021; 73 (3): 459-470