Abstract 11819: Follistatin-like 1, a Muscle-derived Secreted Protein, Reduces Neointimal Hyperplasia and Modulates Smooth Muscle Cell Function
Background: Pathological vascular remodeling is one of crucial steps of various cardiovascular diseases including restenosis after coronary intervention. Smooth muscle cell (SMC) proliferation and migration are key features during vascular remodeling. We have shown that follistatin-like 1 (Fstl1) acts as a muscle-derived secretory factor that exerts beneficial actions on cardiac damage and endothelial function. However, nothing is known about the role of Fstl1 in regulating pathological vascular remodeling. Here, we investigated the effect of Fstl1 on neointimal formation and smooth muscle cell function.
Methods and results: Skeletal muscle-specific Fstl1 transgenic (Tg) mice and wild type (WT) mice were subjected to vascular wire injury. Fstl1-Tg mice showed attenuated neointimal thickenings at 3 weeks after vascular injury compared with WT mice, which was accompanied with decreased proliferative BrdU-positive cells in the neointima. In cultured human aortic SMC (HASMC), treatment with recombinant human Fstl1 protein decreased DNA synthesis and migratory activity induced by platelet derived growth factor (PDGF)-BB, which was accompanied by suppression of extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, treatment of HASMC with human Fstl1 protein increased phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream target, acetyl CoA carboxylase. Transduction of HASMC with an adenoviral vector expressing dominant-negative mutant of AMPK abrogated the inhibitory action of Fstl1 on PDGF-BB-induced DNA synthesis.
Conclusion: Our findings document that skeletal muscle-derived Fstl1 reduces neointimal formation in response to arterial injury through AMPK-dependent mechanism, indicating that Fstl1 may be a novel therapeutic target for prevention of pathological vascular remodeling.
- © 2012 by American Heart Association, Inc.