title: Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome.
abstract: Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.|Department of Biomedical Engineering, The City College of New York, 160 Convent Ave, New York, NY, 10031, USA.
authors.forename: Jia-Jye
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Galatioto
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. kevin.costa@mssm.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D000071838:Fibrillin-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008382:Marfan Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D019808:Losartan; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Atomic force microscopy; Losartan; Lung biomechanics; Marfan syndrome; Vascular biomechanics