title: Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload.
abstract: Fibroblasts, which are the most numerous cell type in the heart, interact with cardiomyocytes in vitro and affect their function; however, they are considered to play a secondary role in cardiac hypertrophy and failure. Here we have shown that cardiac fibroblasts are essential for the protective and hypertrophic myocardial responses to pressure overload in vivo in mice. Haploinsufficiency of the transcription factor-encoding gene Krüppel-like factor 5 (Klf5) suppressed cardiac fibrosis and hypertrophy elicited by moderate-intensity pressure overload, whereas cardiomyocyte-specific Klf5 deletion did not alter the hypertrophic responses. By contrast, cardiac fibroblast-specific Klf5 deletion ameliorated cardiac hypertrophy and fibrosis, indicating that KLF5 in fibroblasts is important for the response to pressure overload and that cardiac fibroblasts are required for cardiomyocyte hypertrophy. High-intensity pressure overload caused severe heart failure and early death in mice with Klf5-null fibroblasts. KLF5 transactivated Igf1 in cardiac fibroblasts, and IGF-1 subsequently acted in a paracrine fashion to induce hypertrophic responses in cardiomyocytes. Igf1 induction was essential for cardioprotective responses, as administration of a peptide inhibitor of IGF-1 severely exacerbated heart failure induced by high-intensity pressure overload. Thus, cardiac fibroblasts play a pivotal role in the myocardial adaptive response to pressure overload, and this role is partly controlled by KLF5. Modulation of cardiac fibroblast function may provide a novel strategy for treating heart failure, with KLF5 serving as an attractive target.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Takeda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Uchino
authors.forename: Kosei
authors.initials: K
authors.lastname: Eguchi
authors.forename: Sahohime
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D007334:Insulin-Like Growth Factor I