title: Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.
abstract: Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Tae
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland petrashevskayn@mail.nih.gov.
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Shannon
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Melissa
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Talan
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000473:pathology; D000071838:Fibrillin-1; D000071837:Fibrillins; D005355:Fibrosis / Q000473:pathology; D006439:Hemodynamics; D020935:MAP Kinase Signaling System; D008297:Male; D008382:Marfan Syndrome / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D008944:Mitral Valve Insufficiency / Q000209:etiology / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse
keywords: Marfan syndrome; cardiac function; fibrillin-1; myocardial hypertrophy