Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice
Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice
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DOI：
10.1152/ajpcell.00433.2007
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发表时间：
2008-07-01
影响因子：
5.5
通讯作者：
Dillmann, Wolfgang H.
中科院分区：
文献类型：
--
作者：
Makino, Ayako;Platoshyn, Oleksandr;Dillmann, Wolfgang H.
血管内皮细胞（EC）在调节血管张力和血管重建中起主要作用。越来越多的证据显示糖尿病患者的内皮功能障碍，尽管对连接蛋白（Cxs）在糖尿病心脏血管并发症中的作用知之甚少。本研究旨在探讨Cxs在糖尿病小鼠冠状动脉内皮功能障碍中的作用。从糖尿病小鼠中分离的冠状动脉EC表现出Cx37和Cx40蛋白水平降低（但不是Cx43）和间隙连接细胞间通讯（GJIC）的损失。在糖尿病冠状动脉（CA）中，由假设的EC依赖性超极化引起的血管舒张显著减少。Cx40特异性抑制肽（40）GAP 27在不影响对照CA中的舒张的浓度下强烈减弱糖尿病CA中的内皮依赖性舒张，表明糖尿病CA中的Cx40总量低于对照CA。在糖尿病小鼠中，体内冠状动脉毛细血管密度显著降低。在体外，GJIC抑制剂减弱EC毛细血管网络形成的能力。高糖处理导致内皮细胞Cx40蛋白表达减少，内皮毛细血管网形成受损，Cx40过表达可恢复内皮毛细血管网形成。此外，我们发现，高血糖诱导的Cx40减少与抑制蛋白质表达的Sp1，一个转录因子，调节Cx40的表达。这些数据表明，下调Cx40蛋白表达和GJIC的抑制有助于糖尿病冠状动脉血管功能障碍。
Vascular endothelial cells (ECs) play a major role in regulating vascular tone and in revascularization. There is increasing evidence showing endothelial dysfunction in diabetes, although little is known about the contribution of connexins (Cxs) to vascular complications in the diabetic heart. This study was designed to investigate the role of Cxs in coronary endothelial dysfunction in diabetic mice. Coronary ECs isolated from diabetic mice exhibit lowered protein levels of Cx37 and Cx40 (but not Cx43) and a loss of gap junction intercellular communication (GJIC). Vasodilatation induced by the assumed contribution of EC-dependent hyperpolarization was significantly reduced in the diabetic coronary artery (CA). Cx40-specific inhibitory peptide (40)GAP27 strongly attenuated endothelium-dependent relaxation in diabetic CA at the concentration that does not affect the relaxation in control CA, suggesting that the total amount of Cx40 is lower in diabetic CA than in control CA. In diabetic mice, coronary capillary density was significantly decreased in vivo. In vitro, GJIC inhibitor attenuated the ability of EC capillary network formation. High-glucose treatment caused a decrease in Cx40 protein expression in ECs and impaired endothelial capillary network formation, which was restored by Cx40 overexpression. Furthermore, we found that the hyperglycemia-induced decrease in Cx40 was associated with inhibited protein expression of Sp1, a transcriptional factor that regulates Cx40 expression. These data suggest that downregulation of Cx40 protein expression and resultant inhibition of GJIC contribute to coronary vascular dysfunction in diabetes.