Open AccessLong‐term miR‐29b suppression reduces aneurysm formation in a Marfan mouse model
Author(s) -
Okamura Homare,
Emrich Fabian,
Trojan Jeffrey,
Chiu Peter,
Dalal Alex R.,
Arakawa Mamoru,
Sato Tetsuya,
Penov Kiril,
Koyano Tiffany,
Pedroza Albert,
Connolly Andrew J.,
Rabinovitch Marlene,
Alvira Cristina,
Fischbein Michael P.
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13257
Subject(s) - aneurysm , marfan syndrome , medicine , elastin , aortic aneurysm , aorta , extracellular matrix , matrix metalloproteinase , therapeutic effect , cardiology , blockade , surgery , urology , pathology , receptor , biology , microbiology and biotechnology
Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR‐29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1 C1039G/+ Marfan mice. Herein, we sought to determine whether miR‐29b suppression can reduce aneurysm formation long‐term. Fbn1 C1039G/+ Marfan mice were treated with retro‐orbital LNA ‐anti‐miR‐29b inhibitor or scrambled‐control‐miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1 C1039G/+ mice at 14.5 days post‐coitum) ( n = 8–10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks ( n = 8–10, each group). To determine if miR‐29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed ( n = 4–6, each group). miR‐29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA ‐anti‐miR‐29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR‐29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR‐29b inhibition significantly reduces aneurysm development long‐term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR‐29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.