Abstract 19986: MicroRNA-29b is a Regulator and Therapeutic Target of Aortic Stiffness in Type 2 Diabetes
Introduction: Accelerated arterial stiffening is a common complication of type 2 diabetes that is patho-mechanistically linked to a severely increased cardiovascular risk. Unfortunately, up to date specific strategies to effectively address diabetic vascular stiffening are elusive. The discovery of non-coding microRNAs (miRs) provides new opportunities for innovative therapeutical approaches. Specifically, microRNA-29b may potentially serve as a comprehensive regulator of vascular fibrosis as well as elastin breakdown, both contributing to diabetic arterial stiffness.
Objective: This study was designed to investigate the role of miR-29b as potential mediator and therapeutic target of diabetic aortic stiffness.
Method and Results: Ex vivo mechanical testing of thoracic aortae via pressure myography revealed increased aortic stiffness in diabetic db/db mice. Vascular stiffening was accompanied by increased elastin fragmentation and collagen deposition (EvG and Picrosirius Red staining). qRT-PCR, in-situ hybridization and immunohistochemistry revealed decreased expression of miR-29b and de-repression of target genes (Col1A1, COL3A1, MMP2, MMP9) in db/db mice compared to controls. Investigating the mechanistic significance of miR-29b for arterial stiffening, forced downregulation of miR-29b (via systemic LNA-miR-29b inhibitor application) results in enhanced elastin fragmentation, increased medial collagen deposition, and increased aortic stiffness. Conversely, miR-29b overexpression (using a in vivo-jetPEI approach) effectively contained diabetic aortic stiffening in db/db mice.
Conclusions: This study identifies miR-29b downregulation in diabetic vessels as a patho-mechanistic driver of vascular fibrosis and elastin fragmentation leading to increased arterial stiffness. Therapeutically, restoration of miR-29b is sufficient to prevent adverse arterial remodeling in the context of diabetes.
Author Disclosures: I.N. Schellinger: None. L. Mattes: None. K. Mattern: None. J.M. Spin: None. L. Maegdefessel: None. G. Hasenfuß: None. P.S. Tsao: None. U. Raaz: None.
- © 2016 by American Heart Association, Inc.