Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus
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Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus. / 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; Hasenfuß, Gerd; Spin, Joshua M; Tsao, Philip S.
in: CIRC RES, Jahrgang 117, Nr. 6, 28.08.2015, S. 513-24.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus
AU - Raaz, Uwe
AU - Schellinger, Isabel N
AU - Chernogubova, Ekaterina
AU - Warnecke, Christina
AU - Kayama, Yosuke
AU - Penov, Kiril
AU - Hennigs, Jan K
AU - Salomons, Florian
AU - Eken, Suzanne
AU - Emrich, Fabian C
AU - Zheng, Wei H
AU - Adam, Matti
AU - Jagger, Ann
AU - Nakagami, Futoshi
AU - Toh, Ryuji
AU - Toyama, Kensuke
AU - Deng, Alicia
AU - Buerke, Michael
AU - Maegdefessel, Lars
AU - Hasenfuß, Gerd
AU - Spin, Joshua M
AU - Tsao, Philip S
N1 - © 2015 American Heart Association, Inc.
PY - 2015/8/28
Y1 - 2015/8/28
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCRESAHA.115.306341
DO - 10.1161/CIRCRESAHA.115.306341
M3 - SCORING: Journal article
C2 - 26208651
VL - 117
SP - 513
EP - 524
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 6
ER -