MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening

• Published in: Molecular therapy. Nucleic acids Vol. 24; pp. 188 - 199
• Main Authors: Schellinger, Isabel N., Wagenhäuser, Markus, Chodisetti, Giriprakash, Mattern, Karin, Dannert, Angelika, Petzold, Anne, Jakubizka-Smorag, Joanna, Emrich, Fabian, Haunschild, Josephina, Schuster, Andreas, Schwob, Elisabeth, Schulz, Kei, Maegdefessel, Lars, Spin, Joshua M., Stumvoll, Michael, Hasenfuß, Gerd, Tsao, Philip S., Raaz, Uwe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: arterial stiffness; collagen; diabetes mellitus; elastin; extracellular matrix; Medicin och hälsovetenskap; microRNA; non-coding RNA; Original; arterial stiffness; non-coding RNA; collagen; microRNA; diabetes mellitus; elastin; extracellular matrix
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2021.02.021

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. [Display omitted] Stiffening of large arteries represents a significant complication in patients with diabetes mellitus resulting in high blood pressure levels and widespread organ damage (in particular in heart, brain, and kidneys). In this study we identify microRNA-29b as a comprehensive regulator and potential therapeutical target of diabetic arterial remodeling and stiffening.