Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice
Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice
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DOI：
10.2337/diabetes.55.03.06.db05-1284
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发表时间：
2006-03-01
期刊：
影响因子：
7.7
通讯作者：
Gómez, AM
中科院分区：
文献类型：
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作者：
Pereira, L;Matthes, J;Gómez, AM
心血管疾病是糖尿病人群死亡的主要原因。然而，糖尿病心肌病的分子机制仍不清楚。我们分析了Ca 2+诱导的Ca 2+释放和兴奋-收缩偶联在db/db肥胖2型糖尿病小鼠和他们的对照同窝。超声心动图显示db/db小鼠的收缩功能障碍。双光子显微镜观察发现整个心脏内心肌细胞内钙离子浓度（[Ca 2 +]（i））短暂降低，共聚焦显微镜观察也发现分离的心肌细胞内钙离子浓度（[Ca 2 +]（i））降低。整体[Ca 2 +]（i）瞬变由单个火花组成。[H-3]ryanodine结合试验显示，db/db心肌细胞的钙火花频率低于+/+心肌细胞，部分原因是肌浆网钙负荷降低，但也因为ryanodine受体钙通道（RyRs）表达减少。db/db心肌细胞Na+/Ca ~（2+）交换器的Ca ~（2+）流出增加。钙电流，I-Ca，触发肌浆网Ca 2+释放，也参与肌浆网Ca 2+再填充。db/db细胞中的宏观I-Ca减少，但单个Ca 2+通道活性相似，表明糖尿病心肌细胞表达较少的功能性Ca 2+通道，这由Western印迹证实。这些结果表明，db/db小鼠表现出心脏功能抑制，至少部分原因是膜对Ca的渗透性普遍降低。随着较少的Ca 2+通过I-Ca进入细胞，较少的Ca 2+通过RyR释放。
Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca2+-induced Ca2+ release and excitation-contraction coupling in db/db obese type 2 diabetic mice and their control littermates. Echocardiography showed a systolic dysfunction in db/db mice. Two-photon microscopy identified intracellular calcium concentration ([Ca2+](i)) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca2+](i) transients are constituted of individual sparks. Ca2+ sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca2+ load but also because of a reduced expression of ryanodine receptor Ca2+ channels (RyRs), revealed by [H-3]ryanodine binding assay. Ca2+ efflux through Na+/Ca2+ exchanger was increased in db/db myocytes. Calcium current, I-Ca, triggers sarcoplasmic reticulum Ca2+ release and is also involved in sarcoplasmic reticulum Ca2+ refilling. Macroscopic I-Ca was reduced in db/db cells, but single Ca2+ channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca2+ channels, which was confirmed by Western blots. These results demonstrate that db/db mice show depressed cardiac function, at least in part, because of a general reduction in the membrane permeability to Ca. As less Ca2+ enters the cell through I-Ca, less Ca2+ is released through RyRs.