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Cardiovasc Res. 2014 Jul 1;103(1):111-20. doi: 10.1093/cvr/cvu105. Epub 2014 Apr 17.

Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury.

Author information

1
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya 466-8550, Japan nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
3
Department of Anatomy, Embryology & Physiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands.
4
Department of Molecular Cardiology, Boston University School of Medicine, Boston, MA, USA.

Abstract

AIMS:

It is well-established that exercise diminishes cardiovascular risk, but whether humoral factors secreted by muscle confer these benefits has not been conclusively shown. We have shown that the secreted protein follistatin-like 1 (Fstl1) has beneficial actions on cardiac and endothelial function. However, the role of muscle-derived Fstl1 in proliferative vascular disease remains largely unknown. Here, we investigated whether muscle-derived Fstl1 modulates vascular remodelling in response to injury.

METHODS AND RESULTS:

The targeted ablation of Fstl1 in muscle led to an increase in neointimal formation following wire-induced arterial injury compared with control mice. Conversely, muscle-specific Fstl1 transgenic (TG) mice displayed a decrease in the neointimal thickening following arterial injury. Muscle-specific Fstl1 ablation and overexpression increased and decreased, respectively, the frequency of BrdU-positive proliferating cells in injured vessels. In cultured human aortic smooth muscle cells (HASMCs), treatment with human FSTL1 protein decreased proliferation and migration induced by stimulation with PDGF-BB. Treatment with FSTL1 enhanced AMPK phosphorylation, and inhibition of AMPK abrogated the inhibitory actions of FSTL1 on HASMC responses to PDGF-BB. The injured arteries of Fstl1-TG mice exhibited an increase in AMPK phosphorylation, and administration of AMPK inhibitor reversed the anti-proliferative actions of Fstl1 on the vessel wall.

CONCLUSION:

Our findings indicate that muscle-derived Fstl1 attenuates neointimal formation in response to arterial injury by suppressing SMC proliferation through an AMPK-dependent mechanism. Thus, the release of protein factors from muscle, such as Fstl1, may partly explain why the maintenance of muscle function can have a therapeutic effect on the cardiovascular system.

KEYWORDS:

AMPK; Fstl1; Myokine; Smooth muscle cell; Vascular remodelling

PMID:
24743592
PMCID:
PMC4834864
DOI:
10.1093/cvr/cvu105
[Indexed for MEDLINE]
Free PMC Article
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