Abstract 17761: Long-term microRNA-29b Suppression Prevents Aneurysm Development in Marfan Syndrome Model Mouse
Objective: Aortic aneurysm and subsequent rupture is the life threatening complication in Marfan syndrome, genetic systemic connective tissue disorder. miR-29b, one of microRNAs, has been reported to be associated with extracellular matrix abnormality in the aortic wall. However, it still remains unclear if miR-29b modulation can prevent the dilation of the aorta. We investigated the effect of long-term miR-29b suppression in the prevention of aneurysm development in a mouse model.
Methods and Results: Fbn1C1039G/+ mouse, Marfan syndrome mouse model, was used. The Fbn1C1039G/+ ascending aorta had larger aortic diameter and more elastin breakdown, compared with that of wild type mouse, correlating with the clinical scenario observed in Marfan syndrome patients. miR-29b was increased during early postnatal development, peaking by 4 weeks, exclusively in the Fbn1C1039G/+ ascending aorta. In order to inhibit miR-29b expression, we treated Fbn1C1039G/+ mice prenatally (single injection at 14.5 days post-coitum) or postnatally (starting at 2 weeks, every other week injection until sacrificed) with a locked nucleic acid-anti-miR-29b inhibitor. miR-29b inhibition resulted in aneurysm prevention, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal treatment prevented aneurysm development up to 32 weeks. On the other hand, postnatal treatment was effective up to 16 weeks but not later than 24 weeks. Postnatal treatment caused fibrosis in the aortic wall at 24 weeks but prenatal treatment did not.
Conclusions: Systemic inhibition of miR-29b, especially prenatal inhibition, significantly prevented the aneurysm development in Marfan syndrome mouse model. The suppression of miR-29b could be a potential therapeutic target for preventing aneurysm formation in Marfan patients.
- © 2013 by American Heart Association, Inc.