Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload

Norifumi Takeda, Ichiro Manabe, Yuichi Uchino, Kosei Eguchi, Sahohime Matsumoto, Satoshi Nishimura, Takayuki Shindo, Motoaki Sano, Kinya Otsu, Paige Snider, Simon Conway, Ryozo Nagai

Research output: Contribution to journalArticle

235 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)254-265
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number1
DOIs
StatePublished - Jan 4 2010

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Fibroblasts
Pressure
Cardiac Myocytes
Cardiomegaly
Heart Failure
Insulin-Like Growth Factor I
Fibrosis
Haploinsufficiency
Hypertrophy
Transcription Factors
Peptides
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Takeda, N., Manabe, I., Uchino, Y., Eguchi, K., Matsumoto, S., Nishimura, S., ... Nagai, R. (2010). Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. Journal of Clinical Investigation, 120(1), 254-265. https://doi.org/10.1172/JCI40295

Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. / Takeda, Norifumi; Manabe, Ichiro; Uchino, Yuichi; Eguchi, Kosei; Matsumoto, Sahohime; Nishimura, Satoshi; Shindo, Takayuki; Sano, Motoaki; Otsu, Kinya; Snider, Paige; Conway, Simon; Nagai, Ryozo.

In: Journal of Clinical Investigation, Vol. 120, No. 1, 04.01.2010, p. 254-265.

Research output: Contribution to journalArticle

Takeda, N, Manabe, I, Uchino, Y, Eguchi, K, Matsumoto, S, Nishimura, S, Shindo, T, Sano, M, Otsu, K, Snider, P, Conway, S & Nagai, R 2010, 'Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload', Journal of Clinical Investigation, vol. 120, no. 1, pp. 254-265. https://doi.org/10.1172/JCI40295
Takeda, Norifumi ; Manabe, Ichiro ; Uchino, Yuichi ; Eguchi, Kosei ; Matsumoto, Sahohime ; Nishimura, Satoshi ; Shindo, Takayuki ; Sano, Motoaki ; Otsu, Kinya ; Snider, Paige ; Conway, Simon ; Nagai, Ryozo. / Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 1. pp. 254-265.
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