Abstract 481: Downregulation of MicroRNA-143 Induces Proximal Aorta Dilatation in C57BL6/J Mice
Background: Thoracic Aortic Aneurysm (TAA) is a silent life-threatening condition which leads to death if not surgically treated. TAA development is secondary to the remodeling of the aortic wall structure due to pathological changes in both vascular smooth muscle cells (VSMC) and extracellular components. The phenotypic switch of VSMC from a contractile to a pathological synthetic state by inducing excessive production of matrix components is associated with the aberrant remodeling of the aorta. MicroRNA (miR)-143 and -145 are critical in controlling VSMC phenotype and are highly expressed in the aorta. In investigating the molecular mechanisms controlling VSMC phenotype we found that accumulation of reactive oxygen species (ROS) linearly correlates with synthetic VSMC accumulation as well as dilatation of the ascending aorta in humans. Furthermore ROS contribute to the onset of TAA in a murine model based on Angiotensin II (AngII) infusion. Interestingly we found that miR-143 is down regulated in patients with aneurysmal aorta. We hypothesized that miR-143 may be regulated by ROS and its down regulation could contribute to TAA development.
Methods: MiR expression, MMP-2, MMP-9, and VSMC markers of phenotype (Vimentin, Elk-1, Myocardin) were tested in human isolated aortic VSMC treated with ROS. C57BL6/J mice were subjected to AngII for 28 days in the presence or absence of LNA-anti-miR-143. Two-dimensional M Mode echocardiography was performed to measure aortic diameter.
Results: ROS treatment of human VSMC induces a dose dependent down regulation of miR-143 and -145 together with up regulation of MMP-2, MMP-9 and VSMC synthetic markers Vimentin and Elk-1. Both miR-143/145 are down regulated in the aneurysmal proximal aorta of C57BL6/J mice treated with AngII. Injection of LNA-anti-miR-143 alone induces dilatation of the proximal aorta but has no effect on AngII induced TAA development.
Conclusion: ROS induced down regulation of miR-143 is involved in the pathological remodeling of the proximal aorta leading to TAA. Understanding the mechanism behind ROS-mediated regulation of miR-143 may unveil new targets for the development of therapeutic strategies against TAA.
Author Disclosures: E. Branchetti: None. B. Rylski: None. P. Poggio: None. E.K. Lai: None. R.C. Gorman: None. J.H. Gorman: None. J.E. Bavaria: None. G. Ferrari: None.
- © 2014 by American Heart Association, Inc.