title: Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β.
abstract: Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Polakit
authors.initials: P
authors.lastname: Teekakirikul
authors.forename: Seda
authors.initials: S
authors.lastname: Eminaga
authors.forename: Okan
authors.initials: O
authors.lastname: Toka
authors.forename: Ronny
authors.initials: R
authors.lastname: Alcalai
authors.forename: Libin
authors.initials: L
authors.lastname: Wang
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Matthew
authors.initials: M
authors.lastname: Nayor
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Konno
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gorham
authors.forename: Cordula M
authors.initials: CM
authors.lastname: Wolf
authors.forename: Jae B
authors.initials: JB
authors.lastname: Kim
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Schmitt
authors.forename: Jefferey D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hoffman
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005355:Fibrosis; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D001973:Bromodeoxyuridine; D019808:Losartan
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