Diabetes downregulates large-conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle.
Diabetes downregulates large-conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle.
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DOI：
10.1161/01.res.0000260182.36481.c9
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发表时间：
2007-03-16
影响因子：
20.1
通讯作者：
Curtis TM
中科院分区：
文献类型：
--
作者：
McGahon MK;Dash DP;Arora A;Wall N;Dawicki J;Simpson DA;Scholfield CN;McGeown JG;Curtis TM
视网膜血管收缩和视网膜血流减少先于糖尿病视网膜病变的发作。糖尿病期间视网膜小动脉张力增加的病理生理机制尚不清楚。正常情况下，局部Ca 2+释放事件（Ca 2+火花）触发大电导Ca 2+激活的K+（BK）通道的激活，其使血管平滑肌细胞（VSMC）过度增殖和松弛，从而引起血管舒张。在本研究中，我们研究了BK通道功能的视网膜VSMCs从链脲佐菌素（STZ）诱导的糖尿病大鼠。BK通道抑制剂Penitrem A使非糖尿病视网膜小动脉（加压至70 mmHg）收缩28%。在糖尿病动物的视网膜小动脉中，咖啡因诱发的BK电流显著降低，即使咖啡因诱发的[Ca 2 +]i释放不受影响。糖尿病细胞的自发BK电流较小，但Ca 2+火花的幅度较大。去极化电压阶跃引起的BK电流幅度在对照组和糖尿病组小动脉中相似，成孔BKα亚基的mRNA表达无变化。糖尿病视网膜VSMCs的BK通道的Ca ~（2+）敏感性明显降低。BKβ1亚基使BK通道复合物对Ca 2+敏感，并且BKβ1的转录和蛋白水平在糖尿病视网膜小动脉中明显降低。在糖尿病细胞中，BK通道的平均开放时间和对他莫昔芬的敏感性降低，这与BKβ1亚基的下调一致。对于糖尿病动物的BK通道，Pen A的阻断效力较低。因此，BK通道的分子组成的变化可以解释早期糖尿病视网膜灌注不足，这一想法对糖尿病高血压的发病机制具有更广泛的意义。
Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca2+ release events (Ca2+-sparks), trigger the activation of large-conductance Ca2+-activated K+(BK)-channels which hyperpolarize and relax vascular smooth muscle cells (VSMCs), thereby causing vasodilatation. In the present study, we examined BK channel function in retinal VSMCs from streptozotocin(STZ)-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted non-diabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca2+]i release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca2+-sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BKα subunit was unchanged. The Ca2+-sensitivity of single BK channels from diabetic retinal VSMCs was markedly reduced. The BKβ1 subunit confers Ca2+-sensitivity to BK channel complexes and both transcript and protein levels for BKβ1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BKβ1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.