Intracellular Ca2+ regulating proteins in vascular smooth muscle cells are altered with type 1 diabetes due to the direct effects of hyperglycemia.
Intracellular Ca2+ regulating proteins in vascular smooth muscle cells are altered with type 1 diabetes due to the direct effects of hyperglycemia.
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DOI：
10.1186/1475-2840-9-8
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发表时间：
2010-02-01
影响因子：
9.3
通讯作者：
Stehno-Bittel L
中科院分区：
文献类型：
--
作者：
Searls YM;Loganathan R;Smirnova IV;Stehno-Bittel L
据报道，糖尿病动物的血管平滑肌细胞(VSMCs)对生理激动剂的反应导致钙瞬变减少。然而，责任机制尚不清楚。对自身免疫性1型糖尿病耐药生物育种(DR-BB)大鼠和链脲佐菌素诱导的大鼠VSMCs的三磷酸肌醇受体(IP3R)和肌浆网钙泵(SERCA2和SERCA3)的水平和分布进行了观察。一般来说，糖尿病动物的主动脉标本中IP3R水平降低，兰尼定受体(RyR)水平显著升高。特定IP3R亚型的重新分布依赖于大鼠模型。在DR-BB糖尿病大鼠的主动脉中，SERCA2的分布比STZ糖尿病大鼠更明显。利用共聚焦显微镜观察的钙敏感荧光载体，对新鲜分散的对照组和糖尿病动物的VSMC内游离钙离子进行了监测。对照组VSMCs的基础荧光水平明显高于胞浆，而糖尿病VSMCs的基础荧光水平基本相同。加压素可诱导对照组大鼠VSMCs内游离钙离子浓度增加，但对糖尿病大鼠VSMC的反应持续时间长且明显钝化。SERCA特异性阻断剂thapsigargin可使正常大鼠VSMCs内游离钙缓慢升高，而糖尿病大鼠VSMCs则明显延迟和延长。为了确定这些变化是否是由于高血糖的直接影响，用高血糖和对照条件下培养的大鼠主动脉平滑肌细胞(A7r5)重复实验。总的来说，他们表现出与糖尿病动物细胞中相同的蛋白质水平和分布的变化，以及对加压素和thapsigargin的钝化的钙反应。这项工作表明，先前报道的糖尿病动物VSMC中钙信号的减少与IP3R钙通道和SERCA蛋白的减少和/或重新分布有关。这些变化可以在高葡萄糖水平的培养中复制。
Diminished calcium (Ca2+) transients in response to physiological agonists have been reported in vascular smooth muscle cells (VSMCs) from diabetic animals. However, the mechanism responsible was unclear. VSMCs from autoimmune type 1 Diabetes Resistant Bio-Breeding (DR-BB) rats and streptozotocin-induced rats were examined for levels and distribution of inositol trisphosphate receptors (IP3R) and the SR Ca2+ pumps (SERCA 2 and 3). Generally, a decrease in IP3R levels and dramatic increase in ryanodine receptor (RyR) levels were noted in the aortic samples from diabetic animals. Redistribution of the specific IP3R subtypes was dependent on the rat model. SERCA 2 was redistributed to a peri-nuclear pattern that was more prominent in the DR-BB diabetic rat aorta than the STZ diabetic rat. The free intracellular Ca2+ in freshly dispersed VSMCs from control and diabetic animals was monitored using ratiometric Ca2+ sensitive fluorophores viewed by confocal microscopy. In control VSMCs, basal fluorescence levels were significantly higher in the nucleus relative to the cytoplasm, while in diabetic VSMCs they were essentially the same. Vasopressin induced a predictable increase in free intracellular Ca2+ in the VSMCs from control rats with a prolonged and significantly blunted response in the diabetic VSMCs. A slow rise in free intracellular Ca2+ in response to thapsigargin, a specific blocker of SERCA was seen in the control VSMCs but was significantly delayed and prolonged in cells from diabetic rats. To determine whether the changes were due to the direct effects of hyperglycemica, experiments were repeated using cultured rat aortic smooth muscle cells (A7r5) grown in hyperglycemic and control conditions. In general, they demonstrated the same changes in protein levels and distribution as well as the blunted Ca2+ responses to vasopressin and thapsigargin as noted in the cells from diabetic animals. This work demonstrates that the previously-reported reduced Ca2+ signaling in VSMCs from diabetic animals is related to decreases and/or redistribution in the IP3R Ca2+ channels and SERCA proteins. These changes can be duplicated in culture with high glucose levels.
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影响因子：
5.5
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通讯作者：
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