Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus.
Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus.
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转录因子RUNX2促进2型糖尿病的主动脉纤维化和刚度。
DOI：
10.1161/circresaha.115.306341
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发表时间：
2015-08-28
影响因子：
20.1
通讯作者：
Tsao PS
中科院分区：
文献类型：
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作者：
Raaz U;Schellinger IN;Chernogubova E;Warnecke C;Kayama Y;Penov K;Hennigs JK;Salomons F;Eken S;Emrich FC;Zheng WH;Adam M;Jagger A;Nakagami F;Toh R;Toyama K;Deng A;Buerke M;Maegdefessel L;Hasenfuß G;Spin JM;Tsao PS
动脉加速硬化是糖尿病的主要并发症，目前尚无专门的治疗方法。本研究探讨了成骨转录因子Runx2作为糖尿病主动脉纤维化和主动脉硬化的潜在介质和治疗靶点的作用。使用2型糖尿病小鼠模型（db/db小鼠），我们发现在动脉高血压发病之前进行性结构性主动脉硬化。同时，Runx2在db/db主动脉内侧层以及2型糖尿病患者的胸主动脉样本中异常上调。转基因小鼠血管平滑肌特异性过表达Runx2增加其靶基因Col1a1和Col1a2的表达，导致内侧纤维化和主动脉硬化。有趣的是，Runx2表达增加本身并不足以诱导主动脉钙化。通过体内和体外实验，我们进一步证明Runx2在糖尿病中的表达是通过氧化还原敏感途径调控的，该途径涉及NF-κB与Runx2启动子的直接相互作用。总之，本研究强调Runx2是一种以前未被认识到的糖尿病血管纤维化诱导剂，促进动脉硬化，而不考虑钙化。
Accelerated arterial stiffening is a major complication of diabetes with no specific therapy available up to date. The present study investigates the role of the osteogenic transcription factor Runx2 as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes. Using a murine model of type 2 diabetes (db/db mice) we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae as well as in thoracic aortic samples from type 2 diabetic patients. Vascular smooth muscle-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that Runx2 expression in diabetes is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter. In conclusion this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes, promoting arterial stiffness irrespective of calcification.