Uwe Raaz1, Isabel N Schellinger1, Ekaterina Chernogubova1, Christina Warnecke1, Yosuke Kayama1, Kiril Penov1, Jan K Hennigs1, Florian Salomons1, Suzanne Eken1, Fabian C Emrich1, Wei H Zheng1, Matti Adam1, Ann Jagger1, Futoshi Nakagami1, Ryuji Toh1, Kensuke Toyama1, Alicia Deng1, Michael Buerke1, Lars Maegdefessel1, Gerd Hasenfuß1, Joshua M Spin1, Philip S Tsao2. 1. From the Division of Cardiovascular Medicine (U.R., I.N.S., Y.K., W.H.Z., M.A., A.J., F.N., R.T., K.T., A.D., J.M.S., P.S.T.), and Cardiovascular Institute (U.R., Y.K., K.P., J.K.H., F.C.E., M.A., A.J., F.N., K.T., J.M.S., P.S.T.), Stanford University School of Medicine, Stanford, CA; VA Palo Alto Health Care System, Palo Alto, CA (U.R., I.N.S., Y.K., W.H.Z., M.A., A.J., K.T., A.D., J.M.S., P.S.T.); Heart Center, Georg-August-University Göttingen, Göttingen, Germany (U.R., G.H.); Departments of Medicine (E.C., S.E., L.M.) and Cell and Molecular Biology (F.S.), Karolinska Institute, Stockholm, Sweden; Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany (C.W.); and Division of Cardiovascular Medicine and Intensive Care Medicine, Saint Mary's Hospital, Siegen, Germany (M.B.). 2. From the Division of Cardiovascular Medicine (U.R., I.N.S., Y.K., W.H.Z., M.A., A.J., F.N., R.T., K.T., A.D., J.M.S., P.S.T.), and Cardiovascular Institute (U.R., Y.K., K.P., J.K.H., F.C.E., M.A., A.J., F.N., K.T., J.M.S., P.S.T.), Stanford University School of Medicine, Stanford, CA; VA Palo Alto Health Care System, Palo Alto, CA (U.R., I.N.S., Y.K., W.H.Z., M.A., A.J., K.T., A.D., J.M.S., P.S.T.); Heart Center, Georg-August-University Göttingen, Göttingen, Germany (U.R., G.H.); Departments of Medicine (E.C., S.E., L.M.) and Cell and Molecular Biology (F.S.), Karolinska Institute, Stockholm, Sweden; Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany (C.W.); and Division of Cardiovascular Medicine and Intensive Care Medicine, Saint Mary's Hospital, Siegen, Germany (M.B.). ptsao@stanford.edu.
Abstract
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.
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.
Authors: Joseph J Boyle; Michael Johns; Theresa Kampfer; Aivi T Nguyen; Laurence Game; Dominik J Schaer; Justin C Mason; Dorian O Haskard Journal: Circ Res Date: 2011-11-03 Impact factor: 17.367
Authors: Mary J Roman; Richard B Devereux; Joseph E Schwartz; Michael D Lockshin; Stephen A Paget; Adrienne Davis; Mary K Crow; Lisa Sammaritano; Daniel M Levine; Beth-Ann Shankar; Elfi Moeller; Jane E Salmon Journal: Hypertension Date: 2005-05-23 Impact factor: 10.190
Authors: Uwe Raaz; Ryuji Toh; Lars Maegdefessel; Matti Adam; Futoshi Nakagami; Fabian C Emrich; Joshua M Spin; Philip S Tsao Journal: Antioxid Redox Signal Date: 2013-09-17 Impact factor: 8.401
Authors: Alexander N Kapustin; Martijn L L Chatrou; Ignat Drozdov; Ying Zheng; Sean M Davidson; Daniel Soong; Malgorzata Furmanik; Pilar Sanchis; Rafael Torres Martin De Rosales; Daniel Alvarez-Hernandez; Rukshana Shroff; Xiaoke Yin; Karin Muller; Jeremy N Skepper; Manuel Mayr; Chris P Reutelingsperger; Adrian Chester; Sergio Bertazzo; Leon J Schurgers; Catherine M Shanahan Journal: Circ Res Date: 2015-02-23 Impact factor: 17.367
Authors: Peter Lanzer; Manfred Boehm; Victor Sorribas; Marc Thiriet; Jan Janzen; Thomas Zeller; Cynthia St Hilaire; Catherine Shanahan Journal: Eur Heart J Date: 2014-04-16 Impact factor: 29.983
Authors: Bradley S Fleenor; Jason S Eng; Amy L Sindler; Bryant T Pham; Jackson D Kloor; Douglas R Seals Journal: Aging Cell Date: 2014-01-21 Impact factor: 9.304
Authors: Bindu Ramachandran; John N Stabley; Su-Li Cheng; Abraham S Behrmann; Austin Gay; Li Li; Megan Mead; Julia Kozlitina; Andrew Lemoff; Hamid Mirzaei; Zhijian Chen; Dwight A Towler Journal: J Biol Chem Date: 2018-04-06 Impact factor: 5.157
Authors: Jakob Voelkl; Rashad Tuffaha; Trang T D Luong; Daniel Zickler; Jaber Masyout; Martina Feger; Nicolas Verheyen; Florian Blaschke; Makoto Kuro-O; Andreas Tomaschitz; Stefan Pilz; Andreas Pasch; Kai-Uwe Eckardt; Juergen E Scherberich; Florian Lang; Burkert Pieske; Ioana Alesutan Journal: J Am Soc Nephrol Date: 2018-04-13 Impact factor: 10.121
Authors: Abraham Behrmann; Dalian Zhong; Li Li; Su-Li Cheng; Megan Mead; Bindu Ramachandran; Parastoo Sabaeifard; Mohammad Goodarzi; Andrew Lemoff; Henry M Kronenberg; Dwight A Towler Journal: Circ Res Date: 2020-03-11 Impact factor: 17.367
Authors: Young S Oh; Dan E Berkowitz; Richard A Cohen; C Alberto Figueroa; David G Harrison; Jay D Humphrey; Douglas F Larson; Jane A Leopold; Robert P Mecham; Nelson Ruiz-Opazo; Lakshmi Santhanam; Francesca Seta; John Y J Shyy; Zhongjie Sun; Philip S Tsao; Jessica E Wagenseil; Zorina S Galis Journal: Circ Res Date: 2017-11-10 Impact factor: 17.367