title: Fibroblast growth factor receptor 1 signaling in adult cardiomyocytes increases contractility and results in a hypertrophic cardiomyopathy.
abstract: Fibroblast growth factors (FGFs) and their receptors are highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. However, it is not known whether cardiomyocyte-expressed FGF receptors are necessary or sufficient for ventricular remodeling in the adult heart. To determine whether cardiomyocytes were competent to respond to an activated FGF receptor, and to determine if this signal would result in the development of hypertrophy, we engineered a doxycycline (DOX)-inducible, cardiomyocyte-specific, constitutively active FGF receptor mouse model (αMHC-rtTA, TRE-caFgfr1-myc). Echocardiographic and hemodynamic analysis indicated that acute expression of caFGFR1 rapidly and directly increased cardiac contractility, while chronic expression resulted in significant hypertrophy with preservation of systolic function. Subsequent histologic analysis showed increased cardiomyocyte cross-sectional area and regions of myocyte disarray and fibrosis, classic features of hypertrophic cardiomyopathy (HCM). Analysis of downstream pathways revealed a lack of clear activation of classical FGF-mediated signaling pathways, but did demonstrate a reduction in Serca2 expression and troponin I phosphorylation. Isolated ventricular myocytes showed enhanced contractility and reduced relaxation, an effect that was partially reversed by inhibition of actin-myosin interactions. We conclude that adult cardiomyocytes are competent to transduce FGF signaling and that FGF signaling is sufficient to promote increased cardiomyocyte contractility in vitro and in vivo through enhanced intrinsic actin-myosin interactions. Long-term, FGFR overexpression results in HCM with a dynamic outflow tract obstruction, and may serve as a unique model of HCM.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Cilvik
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Joy I
authors.initials: JI
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Keita
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Castro
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Gierasch
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America ; Division of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: House
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D006439:Hemodynamics / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1