收稿日期: 2016-04-19
网络出版日期: 2016-06-30
基金资助
国家自然科学基金资助项目(81270222, 81470439); 广东省自然科学基金资助项目(2014A030313635); 广东省医学研究基金资助项目(A2015187)
Macrophage migration inhibitory factor deficiency aggravates cardiac hypertrophy induced by phenylephrine in mice
Received date: 2016-04-19
Online published: 2016-06-30
研究巨噬细胞移动抑制因子(macrophage migration inhibitory factor, MIF)缺失对皮下注射苯肾上腺素(phenylephrine, PE)诱导的小鼠心肌肥厚的影响. 利用MIF敲除(MIFknockout, MIF-KO)小鼠及其野生型对照小鼠, 分别建立皮下注射PE诱导的小鼠心肌肥厚模型. 小动物心脏B超检测到小鼠心脏结构功能的改变. 末端脱氧核苷酸转移酶介导的dUTP缺节末端标记(terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling, TUNEL)法检测到小鼠心肌细胞凋亡. 分别用实时定量逆转录多聚酶链反应(quantitative reverse-transcription-polymerase chain reaction, qRT-PCR)和Western Blot方法检测SOD1, SOD2和Trx2的表达. ①连续3 d 20 mg/(kg·d)皮下注射PE可诱导小鼠发生心肌肥厚, 注射PE诱导MIF-KO小鼠发生心肌肥厚的程度高于野生型对照小鼠; ②TUNEL结果显示, 注射PE诱导MIF-KO小鼠心肌发生凋亡的程度高于野生型对照小鼠; ③注射PE诱导MIF-KO小鼠心肌中SOD1和Trx2表达水平降低, 而且MIF-KO小鼠心肌中Trx2表达水平显著低于野生型对照小鼠. MIF缺失会降低SOD1和Trx2的表达水平, 进而加重苯肾上腺素诱导的小鼠心肌细胞凋亡和心肌肥厚.
关键词： 苯肾上腺素; 心肌肥厚; 心肌细胞; 巨噬细胞移动抑制因子
肖珍, 朱杰宁, 唐春梅, 林秋雄, 胡志琴, 张灼, 符永恒, 张梦珍, 单志新 . 巨噬细胞移动抑制因子缺失加重苯肾上腺素诱导的小鼠心肌肥厚[J]. 上海大学学报(自然科学版), 2016 , 22(3) : 336 -343 . DOI: 10.3969/j.issn.1007-2861.2016.03.011
To investigate the effect of macrophage migration inhibitory factor (MIF) deficiency on the cardiac hypertrophy induced by hypodermic injection of phenylephrine (PE) in mice. A mouse model of cardiac hypertrophy induced by hypodermic injection of PE was established based on MIF-knockout (MIF-KO) mouse and the wide type control (WT) mouse. The left ventricular (LV) structure and function variables were assessed by transthoracic echocardiography. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay was performed to detect cardiomyocyte apoptosis. Expressions of SOD1, SOD2 and Trx2 were determined by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blot assay, respectively. ①A mouse model of cardiac hypertrophy was achieved, induced by hypodermic injection of 20 mg/(kg·d) PE for 3 d. Compared with WT mice, PE injection induced more severe cardiac hypertrophy in MIF-KO mice. ②TUNEL assay revealed that the level of PE injection-induced cardiomyocte apoptosis in the myocardium of MIF-KO mouse was higher than that in WT mice. ③Expressions of SOD1 and Trx2 were significantly decreased in the myocardium of MIF-KO mice after PE injection, and reduction of Trx2 protein in myocardium of MIF-KO mice was more than that in WT mouse. MIF deficiency attenuates the expressions of SOD1 and Trx2, contributing to the aggravation of cardiomyocyte apoptosis and cardiac hypertrophy induced by hypodermic injection of PE in mice.
[1] Grieb G, Merk M, Bernhagen J, et al. Macrophage migration inhibitory factor (MIF): a promising biomarker [J]. Drug News Perspect, 2010, 23: 257-264.
[2] Xu X, Hua Y, Nair S, et al. Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy [J]. Hypertension, 2014, 63: 490-499.
[3] Koga K, Kenessey A, Ojamaa K. Macrophage migration inhibitory factor antagonizes pressure overload-induced cardiac hypertrophy [J]. Am J Physiol Heart Circ Physiol, 2013, 304: H282-H293.
[4] Slawson S E, Roman B B, Williams D S, et al. Cardiac MRI of the normal and hypertrophied mouse heart [J]. Magn Reson Med, 1998, 39: 980-987.
[5] Kleemann R, Kapurniotu A, Frank R W, et al. Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase [J]. J Mol Biol,
1998, 280: 85-102.
[6] Thiele M, Bernhagen J. Link between macrophage migration inhibitory factor and cellular redox regulation [J]. Antioxid Redox Signal, 2005, 7: 1234-1238.
[7] Luedike P, Hendgen-Cotta U B, Sobierajski J, et al. Cardioprotection through Snitros(yl)ation of macrophage migration inhibitory factor [J]. Circulation, 2012, 125: 1880-1889.
[8] Su H, Li J, Menon S, et al. Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice [J]. Circ Res, 2011, 108: 40-50.
[9] Koga K, Kenessey A, Powell S R, et al. Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress [J]. Antioxid Redox
Signal, 2011, 14: 1191-1202.
[10] Miller E J, Li J, Leng L, et al. Macrophage migration inhibitory factor stimulates AMPactivated protein kinase in the ischaemic heart [J]. Nature, 2008, 451: 578-582.
[11] Qi D, Hu X,Wu X, et al. Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia/reperfusion [J]. J Clin Invest, 2009, 119: 3807-3816.
[12] Zhang T T, Takimoto K, Stewart A F, et al. Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensin Ⅱ and phenylephrine [J]. Circ Res, 2001, 88: 476-482.
[13] Maulik S K, Kumar S. Oxidative stress and cardiac hypertrophy: a review [J]. Toxicol Mech Methods, 2012, 22: 359-366.
[14] Sag C M, Santos C X, Shah A M. Redox regulation of cardiac hypertrophy [J]. J Mol Cell Cardiol, 2014, 73: 103-111.
/
| 〈 |
|
〉 |
