Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus

• Published in: Circulation research 2015-08, Vol.117 (6), p.513-524
• Main Authors: Raaz, Uwe, Schellinger, Isabel N, Chernogubova, Ekaterina, Warnecke, Christina, Kayama, Yosuke, Penov, Kiril, Hennigs, Jan K, Salomons, Florian, Eken, Suzanne, Emrich, Fabian C, Zheng, Wei H, Adam, Matti, Jagger, Ann, Nakagami, Futoshi, Toh, Ryuji, Toyama, Kensuke, Deng, Alicia, Buerke, Michael, Maegdefessel, Lars, Hasenfu, Gerd, Spin, Joshua M, Tsao, Philip S
• Format: Article
• Language: English
• Subjects: Aged; Animals; Aorta - metabolism; Aorta - pathology; Cells, Cultured; Core Binding Factor Alpha 1 Subunit - biosynthesis; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Female; Fibrosis; Humans; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Transcription Factors - biosynthesis; Vascular Stiffness - physiology
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.115.306341

RATIONALE:Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date. OBJECTIVE:The present study investigates the role of the osteogenic transcription factor runt-related transcription factor 2 (Runx2) as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes mellitus. METHODS AND RESULTS:Using a murine model of type 2 diabetes mellitus (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 patients with type 2 diabetes mellitus. Vascular smooth muscle cell–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 expression of Runx2 in diabetes mellitus 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 mellitus, promoting arterial stiffness irrespective of calcification.