Loss of Na+,HCO3−-Cotransporter NBCn1 Inhibits Net Acid Extrusion in the Atria and Causes Hypertension-Associated Cardiac Hypertrophy

IF 5.6 2区 医学 Q1 PHYSIOLOGY
María S. Espejo, Alejandro Orlowski, Trine M. Sørensen, Vladimir V. Matchkov, Ernesto A. Aiello, Ebbe Boedtkjer
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引用次数: 0

Abstract

Aim

Metabolic disturbances challenge pH homeostasis in cardiomyocytes. The electroneutral Na+,HCO3-cotransporter NBCn1/Slc4a7 mediates net acid extrusion, and genetic variation in SLC4A7 contributes to human hypertension and cardiovascular risk. Nonetheless, the cardiac consequences of disrupted NBCn1 expression and function remain unclear. Here, we test the hypothesis that NBCn1, either directly or indirectly, influences cardiac structure, contractile function, and electrophysiological properties.

Methods

Based on mice with global loss of NBCn1, we measure intracellular pH in atria and ventricles of the heart (fluorescence microscopy), membrane potential responses (patch clamping), electro- and echocardiographic variables, blood pressure (telemetry), and cardiac dimensions (in vivo and postmortem analyses).

Results

We find that protein and mRNA expression of NBCn1 are more prominent in atrial than in ventricular cardiomyocytes. Disruption of NBCn1 expression lowers Na+,HCO3-cotransport activity more than 50% in atria without significantly influencing net acid extrusion activity of ventricular cardiomyocytes. Loss of NBCn1 is associated with hypertension (blood pressure increased by ~15 mmHg), cardiac hypertrophy (heart/body weight increased by ~10%), and prolonged ventricular isovolumic relaxation time (increased by ~25%). NBCn1 knockout does not affect cardiomyocyte size, collagen content in the heart wall, overall cardiac contractile function, electrophysiological properties of ventricular cardiomyocytes, or the electrocardiogram.

Conclusion

NBCn1 is a main mechanism of Na+,HCO3-cotransport in atrial tissue and contributes substantially to net acid extrusion during intracellular acidification. NBCn1 does not play any major direct role in ventricular cardiomyocytes of unchallenged mice, but global knockout of NBCn1 increases systemic blood pressure and results in the development of cardiac hypertrophy.

Abstract Image

Na+,HCO3−-共转运体NBCn1的缺失抑制心房净酸挤压并导致高血压相关性心脏肥厚
目的代谢紊乱挑战心肌细胞pH稳态。电中性Na+,HCO3−-共转运体NBCn1/Slc4a7介导净酸挤压,Slc4a7的遗传变异与人类高血压和心血管风险有关。然而,NBCn1表达和功能紊乱对心脏的影响尚不清楚。在这里,我们验证了NBCn1直接或间接影响心脏结构、收缩功能和电生理特性的假设。方法:基于NBCn1整体缺失的小鼠,我们测量了心房和心室的细胞内pH值(荧光显微镜),膜电位反应(贴片夹紧),电和超声心动图变量,血压(遥测)和心脏尺寸(体内和死后分析)。结果NBCn1蛋白和mRNA在心房心肌细胞中的表达比在心室心肌细胞中的表达更为显著。NBCn1表达的中断使心房内Na+、HCO3−-共转运活性降低50%以上,但未显著影响心室心肌细胞的净酸挤压活性。NBCn1的缺失与高血压(血压升高~ 15mmhg)、心脏肥厚(心/体重增加~10%)和心室等容松弛时间延长(增加~25%)有关。NBCn1基因敲除不影响心肌细胞大小、心壁胶原含量、心脏整体收缩功能、心室心肌细胞电生理特性或心电图。结论NBCn1是心房组织Na+、HCO3−-共转运的主要机制,在细胞内酸化过程中对净酸挤压有重要作用。NBCn1在未攻毒小鼠的心室心肌细胞中没有任何主要的直接作用,但NBCn1的整体敲除会增加全身血压并导致心脏肥厚的发生。
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来源期刊
Acta Physiologica
Acta Physiologica 医学-生理学
CiteScore
11.80
自引率
15.90%
发文量
182
审稿时长
4-8 weeks
期刊介绍: Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.
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