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

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 (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Circulation Research American Heart Association

Book Volume: 117

Pages Range: 513-24

Journal Issue: 6

DOI: 10.1161/CIRCRESAHA.115.306341

Abstract

Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date.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.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-?B with the Runx2 promoter.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.

Authors with CRIS profile

Christina Warnecke Medizinische Fakultät

Involved external institutions

Stanford University US United States (USA) (US) Georg-August-Universität Göttingen DE Germany (DE) Karolinska Institute SE Sweden (SE) Saint Mary's Hospital US United States (USA) (US)

How to cite

APA:

Raaz, U., Schellinger, I.N., Chernogubova, E., Warnecke, C., Kayama, Y., Penov, K.,... Tsao, P.S. (2015). Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus. Circulation Research, 117(6), 513-24. https://dx.doi.org/10.1161/CIRCRESAHA.115.306341

MLA:

Raaz, Uwe, et al. "Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus." Circulation Research 117.6 (2015): 513-24.

BibTeX: Download