Jones Sandra A, Boyett Mark R, Lancaster Matthew K
Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Circulation. 2007 Mar 13;115(10):1183-90. doi: 10.1161/CIRCULATIONAHA.106.663070. Epub 2007 Mar 5.
The spontaneous activity of pacemaker cells in the sinoatrial (SA) node controls heart rate under normal physiological conditions. Clinical studies have shown the incidence of SA node dysfunction increases with age and occurs with peak prevalence in the elderly population. The present study investigated whether aging affected the expression of Ca(v)1.2 channels and whether these changes could affect pacemaker activity, in turn leading to age-related SA node degeneration.
The SA node region was isolated from the right atrium of guinea pigs between birth and 38 months of age. Immunofluorescence studies showed Ca(v)1.2 protein was present as punctate labeling around the outer membrane of atrial cells but was absent from the center of the SA node. The area lacking Ca(v)1.2-labeled protein progressively increased from 2.06+/-0.1 (mean+/-SEM) mm2 at 1 month to 18.72+/-2.2 mm2 at 38 months (P<0.001). Western blot provided verification that Ca(v)1.2 protein expression within the SA node declined during aging. Functional measurements showed an increased sensitivity to the L-type calcium blocker nifedipine; SA node preparations stopped beating in 100 micromol/L nifedipine at 1 day old, compared with 30 micromol/L at 1 month and 10 micromol/L at 38 months of age. Furthermore, the amplitude of extracellular potentials declined within the center and periphery of the SA node during aging.
The present data show Ca(v)1.2 channel protein decreases concurrently with reduced spontaneous activity of the SA node with increased age, which provides further evidence of mechanisms underlying the age-related deterioration of the cardiac pacemaker.
在正常生理条件下，窦房结中起搏细胞的自发活动控制着心率。临床研究表明，窦房结功能障碍的发生率随年龄增长而增加，在老年人群中患病率最高。本研究调查了衰老是否会影响Ca(v)1.2通道的表达，以及这些变化是否会影响起搏活动，进而导致与年龄相关的窦房结退变。
从出生至38月龄豚鼠的右心房分离出窦房结区域。免疫荧光研究显示，Ca(v)1.2蛋白呈点状标记存在于心房细胞外膜周围，但在窦房结中心不存在。缺乏Ca(v)1.2标记蛋白的区域从1月龄时的2.06±0.1（平均值±标准误）mm²逐渐增加到38月龄时的18.72±2.2 mm²（P<0.001）。蛋白质印迹法证实，衰老过程中窦房结内Ca(v)1.2蛋白表达下降。功能测量显示对L型钙阻滞剂硝苯地平的敏感性增加；1日龄时，窦房结标本在100 μmol/L硝苯地平中停止跳动，而1月龄时为30 μmol/L，38月龄时为10 μmol/L。此外，衰老过程中窦房结中心和周边的细胞外电位幅度下降。
目前的数据表明，随着年龄增长，Ca(v)1.2通道蛋白减少，同时窦房结的自发活动降低，这为心脏起搏器与年龄相关退变的潜在机制提供了进一步证据。
