title: Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome.
abstract: OBJECTIVE
  Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice).
  
  
  RESULTS
  Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFβ-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA.
  
  
  CONCLUSIONS
  By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFβ.
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clayton
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Luca
authors.initials: L
authors.lastname: Carta
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Josephine
authors.initials: J
authors.lastname: Galatioto
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Emily
authors.initials: E
authors.lastname: Chiu
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Carol A
authors.initials: CA
authors.lastname: Nelson
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.).
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Wentworth
authors.affiliation: From the Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY (J.R.C., L.C., J.G., E.C., S.S., F.R.); and Genzyme, a Sanofi Company, Framingham, MA (N.P.C., C.A.N., S.H.C., B.M.W.). francesco.ramirez@mssm.edu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001019:Aortic Rupture / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D054392:Adipokines
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057134:Antibodies, Neutralizing; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D044140:Receptor, Angiotensin, Type 1; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C497783:Smad2 protein, mouse; C535148:Mapk1 protein, mouse
keywords: Marfan syndrome; aortic aneurysm; losartan; receptor, angiotensin, type 1; transforming growth factor β