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Overexpression of Na+-HCO3- cotransporter contributes to the exacerbation of cardiac remodeling in mice with myocardial infarction by increasing intracellular calcium overload.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 6.2 ) Pub Date : 2019-11-26 , DOI: 10.1016/j.bbadis.2019.165623
Zhenhuan Chen 1 , Lu Chen 2 , Kaitong Chen 2 , Hairuo Lin 2 , Mengjia Shen 2 , Lin Chen 2 , Hailin Zhu 2 , Yingqi Zhu 2 , Qiancheng Wang 2 , Fang Xi 3 , Xiaobo Huang 2 , Yuegang Wang 2 , Wangjun Liao 4 , Jianping Bin 2 , Masanori Asakura 5 , Jie Liu 6 , Masafumi Kitakaze 7 , Yulin Liao 2
Affiliation  

The role of the cardiac isoform of the electrogenic sodium-bicarbonate ion cotransporter (NBCe1) in cardiac remodeling is not fully understood. The aim of this study was to assess the effects of NBCe1 overexpression on cardiac remodeling induced by myocardial infarction (MI) in mice. We generated NBCe1 transgenic (Tg) mice and NBCe1 overexpressing adult mouse ventricular myocytes (AMVMs) to investigate the role of NBCe1 on post-MI remodeling and calcium kinetics. Tg mice showed a markedly higher mortality rate and larger infarct size after MI. At 6 weeks after MI, the maximum rising rates of left ventricular pressure (dp/dt), contractility index, and the exponential time constant of relaxation (τ) were markedly lower, and there was higher cardiomyocyte apoptosis, in Tg mice compared with WT mice. In cultured AMVMs, overexpression of NBCe1 decreased sarcomere shortening and calcium amplitude. In WT AMVMs, the rates of the rise and decay phase of calcium transients, indicated by the rising time (Tpeak, time to peak) and decay time constant (τd), and the number of apoptotic cells, were increased following hypoxia, while overexpression of NBCe1 further increased Tpeak and cellular apoptosis, but not τd. Intracellular resting calcium and sodium concentrations were significantly increased following both hypoxia and NBCe1 overexpression. Co-treatment with S0859, an NBCe1 antagonist, blocked the hypoxia-induced increase in Tpeak, τd, intracellular resting calcium and sodium concentrations, and apoptosis in cardiomyocytes. These findings indicate that NBCe1 overexpression promotes cardiac remodeling by increasing intracellular calcium overload. Therefore, NBCe1 should be a potential target for treatment of cardiac remodeling.

中文翻译:

Na + -HCO3-共转运蛋白的过表达通过增加细胞内钙超载而加剧心肌梗死小鼠的心脏重塑。

尚不完全了解心源性碳酸氢钠离子共转运蛋白(NBCe1)在心脏重塑中的作用。这项研究的目的是评估NBCe1过表达对小鼠心肌梗死(MI)诱导的心脏重塑的影响。我们生成了NBCe1转基因(Tg)小鼠和过表达NBCe1的成年小鼠心室肌细胞(AMVMs),以研究NBCe1对MI后重塑和钙动力学的作用。Tg小鼠在MI后显示出明显更高的死亡率和更大的梗塞面积。在MI后6周,与WT相比,Tg小鼠的最大左室压力上升速率(dp / dt),收缩指数和舒张指数时间常数(τ)显着降低,并且心肌细胞凋亡更高老鼠。在培养的AMVM中,NBCe1的过表达减少了肌节缩短和钙振幅。在WT AMVM中,缺氧后钙瞬变的上升和衰减阶段的速率(由上升时间(峰值,到达峰的时间)和衰减时间常数(τd)指示)和凋亡细胞的数量增加,而过表达NBCe1的增加进一步增加了Tpeak和细胞凋亡,但没有增加τd。缺氧和NBCe1过表达后,细胞内静息钙和钠浓度显着增加。与NBCe1拮抗剂S0859共同治疗可阻止低氧诱导的Tpeak,τd,细胞内静息钙和钠浓度增加以及心肌细胞凋亡。这些发现表明,NBCe1过表达通过增加细胞内钙超载促进心脏重塑。所以,
更新日期:2019-11-26
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