Tribbles 3: A potential player in diabetic aortic remodelling
Tribbles 3: A potential player in diabetic aortic remodelling
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DOI：
10.1177/1479164115605645
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发表时间：
2016-01
影响因子：
2.4
通讯作者：
Y. Ti;Guo-lu Xie;Zhi-hao Wang;Wen Y. Ding;Yun Zhang;M. Zhong;Wei Zhang
中科院分区：
文献类型：
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作者：
Y. Ti;Guo-lu Xie;Zhi-hao Wang;Wen Y. Ding;Yun Zhang;M. Zhong;Wei Zhang
Tribbles 3在胰岛素抵抗中表达上调，我们在前期研究中证实其参与糖尿病性心肌病的发生。然而，目前尚不清楚Tribbles 3是否在糖尿病的导管动脉（如主动脉）中起作用。采用高脂饮食和低剂量链脲佐菌素建立2型糖尿病大鼠模型。通过对糖尿病大鼠主动脉壁结构的连续超声检查和组织病理学分析，评价糖尿病大鼠的特征。糖尿病大鼠表现为主动脉内侧厚度增加，胶原沉积过多，弹性纤维减少，血管顺应性降低，并伴有Tribbles 3过表达。为了进一步研究Tribbles 3在主动脉重构中的作用，我们在糖尿病发病12周后对Tribbles 3基因进行了体内沉默。Tribbles 3的沉默可显著逆转病理性主动脉重构，无血压改变。Tribbles 3-小干扰RNA组中膜厚度和血管周围纤维化明显减少；此外，胶原含量和胶原/弹性蛋白比显著降低，导致动脉顺应性改善。此外，随着Tribbles 3的沉默，PI3K/Akt的磷酸化水平降低，MKK4/JNK的激活水平升高。Tribbles 3沉默在介导主动脉重构逆转中是有效的，这意味着Tribbles 3被认为是糖尿病血管并发症的潜在治疗靶点。
Tribbles 3, whose expression is up-regulated by insulin resistance, was confirmed to be involved in diabetic cardiomyopathy in our previous study. However, it is not known whether Tribbles 3 has a role on conduit arteries such as the aorta in diabetes. Type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of diabetic rats by serial ultrasonography and histopathologic analyses of aortic wall architecture. Diabetic rats displayed increased aortic medial thickness, excessive collagen deposition, diminished elastic fibres and reduced vascular compliance together with Tribbles 3 overexpression. To further investigate the role of Tribbles 3 in aortic remodelling, we used Tribbles 3 gene silencing in vivo 12 weeks after onset of diabetes. Silence of Tribbles 3 significantly reversed pathological aortic remodelling without blood pressure modification. In Tribbles 3-small interfering RNA group, medial thickness and perivascular fibrosis were markedly decreased; moreover, there were prominent reductions in collagen content and collagen/elastin ratio, resulting in an improved arterial compliance. Additionally, with Tribbles 3 silencing, the diminished phosphorylation of PI3K/Akt was restored, and increased activation of MKK4/JNK was decreased. Silence of Tribbles 3 is potent in mediating reversal of aortic remodelling, implicating that Tribbles 3 is proposed to be a potential therapeutic target for vascular complication in diabetes.