Sheu Jiunn-Jye, Tsai Tzu-Hsien, Chang Li-Teh, Chiang Chiang-Hua, Youssef Ali A, Sun Cheuk-Kwan, Chang Nyuk-Kong, Yip Hon-Kan
Department of Cardiovascular Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.
Chang Gung Med J. 2008 Mar-Apr;31(2):136-44.
Diabetes mellitus (DM) plays a crucial role in the pathogenesis of initiation and propagation of atherosclerosis. Although previous studies have suggested that interactions between cells form the framework for understanding the pathogenesis of atherosclerosis, little is known about how DM impacts intercellular communication within arteries, which occurs via connexin43 (Cx43) gap junctions (GJs). This study tested the hypothesis that DM suppresses expression of Cx43 GJs, and that this suppression can be abrogated via simvastatin or losartan treatment.
An experimental model of DM (induced by streptozocin 60 mg/kg body weight) in adult male rats (n = 24) was utilized to investigate Cx43 expression in the aorta. These rats were divided into group I (insulin therapy only), group II (insulin plus simvastatin 20 mg/kg/day) and group III (insulin plus losartan 20 mg/kg/day). Twenty-four diabetic rats and 8 healthy rats (group IV) were sacrificed 3 weeks after DM induction for Western blot and immunofluorescence analysis.
By day 21, the blood sugar level was significantly higher than the respective baseline values in groups I, II and III (all values of p < 0.0001). Additionally, the final blood sugar levels of groups I-III were significantly higher than that of group IV (p < 0.0001). The final body weight in group IV was significantly higher than that in groups I-III (all values of p < 0.0001). Experimental results demonstrated that Cx43 expression in the aortic wall did not differ among groups II-IV (p > 0.1). However, compared with groups II-IV, Cx43 expression in the aortic wall was significantly mitigated in group I (all values of p < 0.05). Western blot results showed that relative density of Cx43 to beta-actin was significantly higher in groups II-IV than in group I (p < 0.01).
DM markedly suppressed expression of Cx43 in rat aortic walls. Both simvastatin and losartan treatment significantly reversed the effects of DM on integrity of Cx43 expression.
糖尿病（DM）在动脉粥样硬化的起始和发展发病机制中起关键作用。尽管先前的研究表明细胞间相互作用构成了理解动脉粥样硬化发病机制的框架，但关于DM如何影响通过连接蛋白43（Cx43）间隙连接（GJs）在动脉内发生的细胞间通讯知之甚少。本研究检验了以下假设：DM抑制Cx43 GJs的表达，且这种抑制可通过辛伐他汀或氯沙坦治疗消除。
利用成年雄性大鼠（n = 24）的DM实验模型（通过链脲佐菌素60 mg/kg体重诱导）研究主动脉中Cx43的表达。这些大鼠被分为I组（仅胰岛素治疗）、II组（胰岛素加辛伐他汀20 mg/kg/天）和III组（胰岛素加氯沙坦20 mg/kg/天）。DM诱导3周后，处死24只糖尿病大鼠和8只健康大鼠（IV组）用于蛋白质免疫印迹和免疫荧光分析。
到第21天，I、II和III组的血糖水平显著高于各自的基线值（所有p值<0.0001）。此外，I - III组的最终血糖水平显著高于IV组（p < 0.0001）。IV组的最终体重显著高于I - III组（所有p值<0.0001）。实验结果表明，II - IV组主动脉壁中Cx43的表达无差异（p > 0.1）。然而，与II - IV组相比，I组主动脉壁中Cx43的表达显著降低（所有p值<0.05）。蛋白质免疫印迹结果显示，II - IV组中Cx43与β - 肌动蛋白的相对密度显著高于I组（p < 0.01）。
DM显著抑制大鼠主动脉壁中Cx43的表达。辛伐他汀和氯沙坦治疗均显著逆转了DM对Cx43表达完整性的影响。
