Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model.
Homare Okamura,Fabian Emrich,Jeffrey Trojan,Peter Chiu,Alex R. Dalal,Mamoru Arakawa,Tetsuya Sato,Kiril Penov,Tiffany K Koyano,Albert J. Pedroza,Andrew J. Connolly,Marlene Rabinovitch,Cristina M. Alvira,Michael P. Fischbein +13 more
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TLDR
Systemic miR‐29b inhibition significantly reduces aneurysm development long‐term in a Marfan mouse model and could be a potential therapeutic target for reducing aneurYSm formation in Marfan syndrome patients.Abstract:
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 Fbn1C1039G/+ Marfan mice. Herein, we sought to determine whether miR-29b suppression can reduce aneurysm formation long-term. Fbn1C1039G/+ 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 Fbn1C1039G/+ 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.read more
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TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections
TL;DR: The current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders is presented and the TGF-β paradox is discussed.
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Marfan syndrome; a connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness
TL;DR: The finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.
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Role of Noncoding RNAs in the Pathogenesis of Abdominal Aortic Aneurysm.
TL;DR: In this paper, the role of non-coding RNAs and their target genes focusing on their role in abdominal aortic aneurysm (AAA) was reviewed. And the potential role of microRNAs and long noncodingRNAs as clinical biomarkers and therapeutics was discussed.
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Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.
Jorge Oller,Enrique Gabandé-Rodríguez,María Jesús Ruiz-Rodríguez,Gabriela Desdín-Micó,Juan F. Aranda,Raquel Rodrigues-Díez,Constanza Ballesteros-Martinez,Eva Maria Blanco,Raquel Roldan-Montero,Pedro Acuña,Alberto Forteza Gil,Carlos E. Martín-López,J. Francisco Nistal,Christian L. Lino Cardenas,Mark Evan Lindsay,José Luis Martín-Ventura,Ana M. Briones,Juan Miguel Redondo,María Mittelbrunn +18 more
TL;DR: Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular ma...
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