Functional and molecular evidence for impairment of calcium-activated potassium channels in type-1 diabetic cerebral artery smooth muscle cells
Functional and molecular evidence for impairment of calcium-activated potassium channels in type-1 diabetic cerebral artery smooth muscle cells
复制标题
1型糖尿病脑动脉平滑肌细胞钙激活钾通道受损的功能和分子证据
DOI：
10.1038/sj.jcbfm.9600536
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发表时间：
2008-02-01
影响因子：
6.3
通讯作者：
Wang, Yong-Xiao
中科院分区：
文献类型：
--
作者：
Dong, Ling;Zheng, Yun-Min;Wang, Yong-Xiao
脑血管功能障碍和相关疾病通常发生在1型糖尿病中，但其潜在机制在很大程度上尚不清楚。在这项研究中，我们试图通过膜片钳、分子生物学和遗传学方法来确定链脲佐菌素诱导的1型糖尿病小鼠血管(大脑动脉)平滑肌细胞(CASMCs)的大电导、钙激活的K+(BK)通道是否受损。结果表明，糖尿病大鼠CASMCs自发性瞬间外向电流(STOCs)的频率和幅度显著降低，而自发性钙火花活动显著增加。在糖尿病心肌细胞中，BK通道对电压、钙离子和特异性抑制物伊贝里奥毒素的敏感性均降低。糖尿病小鼠对脑血管中的硫杆菌毒素和血压升高的反应表现为肌源性张力增加和收缩减少。糖尿病脑动脉中BK通道β1的表达显著减少，而不是阿尔法亚单位蛋白的表达。糖尿病对BK通道β1亚单位基因缺失的小鼠CASMCs的BK通道活性的损害是缺失的。总之，BK通道β1亚单位在1型糖尿病血管平滑肌细胞中受损，导致血管收缩增加和血压升高，从而导致1型糖尿病的血管疾病。
Cerebral vascular dysfunction and associated diseases often occur in type-1 diabetes, but the underlying mechanisms are largely unknown. In this study, we sought to determine whether big-conductance, Ca2+-activated K+ (BK) channels were impaired in vascular (cerebral artery) smooth muscle cells (CASMCs) from streptozotocin-induced type-1 diabetic mice using patch clamp, molecular biologic, and genetic approaches. Our data indicate that the frequency and amplitude of spontaneous transient outward currents (STOCs) are significantly decreased, whereas the activity of spontaneous Ca2+ sparks is increased, in diabetic CASMCs. The sensitivity of BK channels to voltage, Ca2+, and the specific inhibitor iberiotoxin are all reduced in diabetic myocytes. Diabetic mice show increased myogenic tone and decreased contraction in response to iberiotoxin in cerebral arteries and elevated blood pressure. The expression of the BK channel beta 1, but not alpha-subunit protein, is markedly decreased in diabetic cerebral arteries. Diabetic impairment of BK channel activity is lost in CASMCs from BK channel beta 1-subunit gene deletion mice. In conclusion, the BK channel beta 1-subunit is impaired in type-1 diabetic vascular SMCs, resulting in increased vasoconstriction and elevated blood pressure, thereby contributing to vascular diseases in type-1 diabetes.