Remodeling of T-tubules and reduced synchrony of Ca2+ release in myocytes from chronically ischemic myocardium
Remodeling of T-tubules and reduced synchrony of Ca2+ release in myocytes from chronically ischemic myocardium
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DOI：
10.1161/circresaha.107.160085
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发表时间：
2008-02-15
影响因子：
20.1
通讯作者：
Sipido, Karin
中科院分区：
文献类型：
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作者：
Heinzel, Frank R.;Bito, Virginie;Sipido, Karin
在心室心肌细胞中，t小管密度是肌浆网（SR） Ca2+释放同步性的重要决定因素，并可能参与缺血性心肌病中SR Ca2+释放减少。因此，我们研究了猪的t小管密度和SR Ca2+释放特性，在诱导严重的旋冠状动脉狭窄（91 +/- 3%,N = 13）并心肌梗死（占左心室总质量8.8 +/- 2.0%）6周后。磁共振和多普勒心肌速度成像显示梗死区及邻近心肌功能严重失调。将从相邻心肌分离的肌细胞与体重匹配的对照猪同一区域的肌细胞进行比较。二-8- anepps（二-8-丁基氨基乙烯-吡啶-丙基磺酸）肌层染色测定的t小管密度降低了27 +/- 7% （P < 0.05）。SR Ca2+释放的同同性（全细胞电压钳期间的共聚焦线扫描图像）在心肌细胞中减少。延迟释放（即半最大[Ca2+](i)发生在20 ms之后）发生在心肌梗死的35.5 +/- 6.4%的扫描线上，而对照组为22.7 +/- 2.5% (P < 0.05)，延长了线平均[Ca2+](i)瞬态峰值的时间（对照组为121 +/- 9 ms，而对照组为102 +/- 5 ms， P < 0.05）。延迟释放与t小管稀疏区域共定位，不能通过蛋白激酶a的激活来抑制。全细胞平均[Ca2+] i瞬态振幅降低，而l型Ca2+电流密度不变，SR含量增加，表明Ca2+诱导的Ca2+释放增益降低。总之，缺血重塑过程中t小管密度的降低与Ca2+释放的同步性降低以及Ca2+内流与Ca2+释放的耦合效率降低有关。
In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca2+ release and could be involved in the reduced SR Ca2+ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca2+ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91 +/- 3%, N = 13) with myocardial infarction (8.8 +/- 2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-aminonaphthylethylene- pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27 +/- 7% ( P < 0.05). Synchrony of SR Ca2+ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, half-maximal [Ca2+](i) occurring later than 20 ms) occurred at 35.5 +/- 6.4% of the scan line in myocardial infarction versus 22.7 +/- 2.5% in control pigs (P < 0.05), prolonging the time to peak of the line-averaged [Ca2+](i) transient (121 +/- 9 versus 102 +/- 5 ms in control pigs, P < 0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca2+] i transient amplitude was reduced, whereas L-type Ca2+ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca2+-induced Ca2+ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca2+ release and reduced efficiency of coupling Ca2+ influx to Ca2+ release.