Endothelial dysfunction plays an essential role in initiation and progression of atherosclerotic diseases. Maintenance of functional integrity of endothelium requires coordination of activities between the individual cells through different mechanisms, one of which is mediated via gap junction channels made of connexin molecules. In vascular endothelium gap junctions contain up to 3 types of connexins that is connexin37 (Cx37), Cx40, and Cx43.
To understand the role of endothelial gap junctions in the process of atherosclerosis we have been investigating the impact of atherogenic factors on the expression of endothelial connexins using animal models and cell culture systems. In the animal experiments, we have demonstrated that endothelial cell gap junctions are down-regulated during the ageing process, in response to hypertension, and in the hyperlipidemic state. In addition, development of diabetes in the hyperlipidemic state further down-regulates the connexins. In contrast, in the regenerating arterial endothelial cells, gap junctions made of the 3 connexins are abundantly expressed near the complete recovery stage. Interestingly, in these studies, individual connexins have distinct responses, which indicate that regulation of each member of endothelial connexins is not the same.
On the other hand, the cultured endothelial cells predominately express Cx43. In the in vitro experiments, Cx43 gap junctions are down-regulated by nicotine as well as arsenic, associated with attenuated gap-junctional communication. For both studies, the down-regulation disappears in the presence of protease inhibitors, implying enhancement of the proteolysis pathway is involved in the action of both atherogens.
In the above in vivo and in vitro studies, we also examined the effects of pharmacological intervention. We found that statins and carvedilol, drugs known to be beneficial to endothelial function, reverse the down-regulation. Finally, in human studies, we have discovered that Cx37 polymorphism is associated with coronary artery disease in Taiwan.
These results indicate that endothelial gap junctions are highly involved in atherogenesis and suggest that down-regulation of endothelial gap junction may be used as a marker of endothelial dysfunction. In addition, development of drugs targeting at the maintenance of endothelial gap junction may benefit patients with atherosclerotic disease.
内皮功能完整性的维持需要通过细胞间不同的机制调整其活性。其中之一是通过以连接素分子为主要成分的缝隙连接信道介导的。在血管内皮中，缝隙连接包括至少三种连接素，即连接素37（Cx37）、Cx40和Cx43。
为了更好的理解内皮缝隙连接在动脉粥样硬化症中的作用，我们已经在动物模型和体外细胞培养实验中研究了导致动脉粥样硬化的因素对内皮连接素表达的影响。在动物实验中，我们证明了在老龄化过程中高血压和高脂血症会导致内皮细胞的缝隙连接下调。另外，在高脂血症时糖尿病的发生进一步下调连接素。相比之下，动脉内皮细胞新生时由三种连接素组成的缝隙连接大量表达，接近完全修复状态。很有意思的是，在这些研究中，连接素的表达存在个体差异，提示内皮连接素的调控是不同的。
另外，培养的内皮细胞主要表达Cx43。在体外实验中，烟碱和砷的作用使Cx43缝隙连接下调，从而消弱了缝隙连接通讯。在这两方面的研究中，蛋白酶抑制剂可以抑制下调现象提示蛋白水解酶通路的加强可以影响动脉粥样硬化发生。
在以上的体内和体外研究中，我们还检测了药理学干预的效应。我们发现他仃和卡维地洛这两种已经明确对内皮功能有利的药物也可以阻止下调现象的发生。最后，在人体研究中，我们发现台湾地区的冠状动脉疾病与Cx37的多态性相关。
这些结果说明内皮缝隙连接与动脉粥样硬化的发生高度相关，提示我们可以把内皮缝隙连接下调作为内皮功能障碍的一个标志。而且，稳定缝隙连接的药物的发展可以给动脉粥样硬化疾病的患者带来福音。
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