Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes
Rationale: Accelerated arterial stiffening is a major complication of diabetes with no specific therapy available up to date.
Objective: 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.
Methods and Results: 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.
Conclusions: 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.
- Received February 27, 2015.
- Revision received July 23, 2015.
- Accepted July 24, 2015.