Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture

Sonomi Maruyama, Kazuto Nakamura, Kyriakos N. Papanicolaou, Soichi Sano, Ippei Shimizu, Yasuhide Asaumi, Maurice J. van den Hoff, Noriyuki Ouchi, Fabio Anastasio Recchia, Kenneth Walsh

Research output: Contribution to journalArticlepeer-review

Abstract

Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI. Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4-expressing fibroblast lineage cells (Fstl1-cfKO mice) led to a reduction in injury-induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1-cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1.

Original languageEnglish (US)
Pages (from-to)949-966
Number of pages18
JournalEMBO Molecular Medicine
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Keywords

  • cardiokine
  • fibrosis
  • infarct healing
  • myocardial infarction

ASJC Scopus subject areas

  • Molecular Medicine

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