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

作者：Miyabe Megumi; Ohashi Koji^*; Shibata Rei; Uemura Yusuke; Ogura Yasuhiro; Yuasa Daisuke; Kambara Takahiro; Kataoka Yoshiyuki; Yamamoto Takashi; Matsuo Kazuhiro; Joki Yusuke; Enomoto Takashi; Hayakawa Satoko; Hiramatsu Ito Mizuho; Ito Masanori; Van den Hoff Maurice J B; Walsh Kenneth; Murohara Toyoaki; Ouchi Noriyuki

来源：Cardiovascular Research, 2014, 103(1): 111-120.

DOI：10.1093/cvr/cvu105

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

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.
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.
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.

• 出版日期2014-7-1