Kostin Sawa, Dammer Sebastian, Hein Stefan, Klovekorn Wolf P, Bauer Erwin P, Schaper Jutta
Department of Experimental Cardiology, Max-Planck-Institute, Benekestr. 2D-61231, Bad Nauheim, Germany.
Cardiovasc Res. 2004 May 1;62(2):426-36. doi: 10.1016/j.cardiores.2003.12.010.
Gap junctions (GJ) are important determinants of conduction. In advanced heart failure alterations of the major ventricular GJ protein, connexin 43 (Cx43) are found. However, changes in Cx43 expression during the progression from compensated cardiac hypertrophy to heart failure, especially in humans, have not been studied extensively. The aim of the present study was to investigate changes in Cx43 expression and distribution in compensated and decompensated left ventricular (LV) hypertrophy in pressure-overloaded human hearts with valvular aortic stenosis (AS).
We measured Cx43 levels by Western blot and quantitative immunoconfocal microscopy of LV septum biopsies from three groups of patients with AS (group I (n=9): ejection fraction (EF)>50%; group II (n=12): EF 30-50%; group III (n=9): EF<30%). LV biopsies from six patients with mitral valve stenosis and two donor hearts served as controls.
Only the early phase of LV hypertrophy (AS-I) was characterized by extensive Cx43 lateral staining. As compared to controls, the AS-I group showed a 44.3% increase in Cx43 protein, which was reflected in an augmented number of GJs per 100 microm(2) intercalated disc area (control: 62.5+/-6.4 vs. AS-I: 79.8+/-4, p<0.001) and an increased GJ surface density (control: 0.00547 vs. AS-I: 0.00724 microm(2)/microm(3), p<0.01). Decompensated LV hypertrophy (AS-III) was specified by reduced percentage of the Cx43 signal per myocyte area (control: 1.74% vs. AS-III: 1.31%, p<0.01) or per intercalated disc (control: 18.3% vs. AS-III: 11.3%, p<0.005). Mean GJ area and GJ number per intercalated discs in the AS-III group were decreased significantly by, respectively, 42.5% and 36.4% as compared to control. In addition, decompensated LV myocardium showed a markedly heterogeneous spatial distribution of Cx43.
The quantity and spatial distribution of Cx43 differs markedly between compensated and decompensated LV hypertrophy in human patients with AS. Upregulation of Cx43 in compensated hypertrophy may represent the immediate adaptive response to increased load, whereas diminished and heterogeneous Cx43 distribution in decompensated hypertrophy may play maladaptive roles culminating in heart failure and ventricular arrhythmias.
缝隙连接（GJ）是传导的重要决定因素。在晚期心力衰竭中，可发现主要的心室GJ蛋白——连接蛋白43（Cx43）发生改变。然而，从代偿性心肌肥厚进展到心力衰竭过程中Cx43表达的变化，尤其是在人类中的变化，尚未得到广泛研究。本研究的目的是调查在患有瓣膜性主动脉狭窄（AS）的压力超负荷人类心脏中，代偿性和失代偿性左心室（LV）肥厚时Cx43表达和分布的变化。
我们通过蛋白质免疫印迹法以及对三组AS患者（I组（n = 9）：射血分数（EF）>50%；II组（n = 12）：EF 30 - 50%；III组（n = 9）：EF<30%）的左心室间隔活检组织进行定量免疫共聚焦显微镜检查来测量Cx43水平。来自六名二尖瓣狭窄患者的左心室活检组织和两个供体心脏作为对照。
只有左心室肥厚的早期阶段（AS - I）以广泛的Cx43侧向染色为特征。与对照组相比，AS - I组的Cx43蛋白增加了44.3%，这反映在每100平方微米闰盘面积中GJ数量增加（对照组：62.5±6.4 vs. AS - I组：79.8±4，p<0.001）以及GJ表面密度增加（对照组：0.00547 vs. AS - I组：0.00724平方微米/立方微米，p<0.01）。失代偿性左心室肥厚（AS - III）的特征是每个心肌细胞面积（对照组：1.74% vs. AS - III组：1.31%，p<0.01）或每个闰盘（对照组：18.3% vs. AS - III组：11.3%，p<0.005）中Cx43信号的百分比降低。与对照组相比，AS - III组中每个闰盘的平均GJ面积和GJ数量分别显著减少了42.5%和36.4%。此外，失代偿性左心室心肌显示出Cx43明显的异质性空间分布。
在患有AS的人类患者中，代偿性和失代偿性左心室肥厚之间Cx43的数量和空间分布存在显著差异。代偿性肥厚中Cx43的上调可能代表对负荷增加的即时适应性反应，而失代偿性肥厚中Cx43分布的减少和异质性可能起不良适应作用，最终导致心力衰竭和室性心律失常。
