MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening

Isabel N Schellinger; Markus Wagenhäuser; Giriprakash Chodisetti; Karin Mattern; Angelika Dannert; Anne Petzold; Joanna Jakubizka-Smorag; Fabian Emrich; Josephina Haunschild; Andreas Schuster; Elisabeth Schwob; Kei Schulz; Lars Maegdefessel; Joshua M Spin; Michael Stumvoll; Gerd Hasenfuß; Philip S Tsao; Uwe Raaz

doi:10.1016/j.omtn.2021.02.021

MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening

Mol Ther Nucleic Acids. 2021 Feb 24:24:188-199. doi: 10.1016/j.omtn.2021.02.021. eCollection 2021 Jun 4.

Authors

Isabel N Schellinger^{1

2

3}, Markus Wagenhäuser⁴, Giriprakash Chodisetti¹, Karin Mattern¹, Angelika Dannert¹, Anne Petzold¹, Joanna Jakubizka-Smorag¹, Fabian Emrich^{5

6}, Josephina Haunschild⁶, Andreas Schuster^{1

2}, Elisabeth Schwob⁷, Kei Schulz⁷, Lars Maegdefessel^{8

9}, Joshua M Spin^{10

11}, Michael Stumvoll³, Gerd Hasenfuß^{1

2}, Philip S Tsao^{10

11}, Uwe Raaz^{1

2}

Affiliations

¹ Department of Cardiology and Pneumology, Heart Center at the University Medical Center Göttingen, Göttingen, Germany.
² German Center for Cardiovascular Research (DZHK) e.V., Partner site Göttingen, Göttingen, Germany.
³ Department for Endocrinology, Nephrology and Rheumatology, University Medical Center Leipzig, University of Leipzig, Leipzig, Germany.
⁴ Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁵ Department of Cardiothoracic and Vascular Surgery, Goethe University Hospital Frankfurt, Frankfurt, Germany.
⁶ Department of Cardiac Surgery, Heart Center Leipzig, Leipzig, Germany.
⁷ Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany.
⁸ Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
⁹ Karolinska Institute, Department of Medicine, Stockholm, Sweden.
¹⁰ Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ VA Palo Alto Health Care System, Palo Alto, CA, USA.

Abstract

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive-and therefore powerful-regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.

Keywords: arterial stiffness; collagen; diabetes mellitus; elastin; extracellular matrix; microRNA; non-coding RNA.