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

Sonomi Maruyama,Ippei Shimizu,Noriyuki Ouchi,Fabio A Recchia,Kyriakos N Papanicolaou,Kazuto Nakamura,Soichi Sano,Kenneth Walsh,Maurice J Van Den Hoff,Yasuhide Asaumi

doi:10.15252/emmm.201506151

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.

Highlights

The drive to identify new biomarkers and therapeutic targets for heart disease has led to increased interest in understanding the regulation and function of the cardiac secretome
The community incidence of ST elevation myocardial infarction (STEMI) has been decreasing, complications of acute MI remain as major life-threatening problems that require intensive treatment (Yeh et al, 2010)
We show that cardiac fibroblasts are a functionally significant source of the secreted glycoprotein Follistatin-like 1 (Fstl1) in a murine model of MI and that the loss of Fstl1 from this cellular compartment leads to an increase in mortality due to cardiac rupture in the acute phase

Summary

Introduction

The drive to identify new biomarkers and therapeutic targets for heart disease has led to increased interest in understanding the regulation and function of the cardiac secretome. Fstl was initially identified as transforming growth factor-beta 1 (TGF-b1)-induced protein in a murine osteoblastic cell line (Shibanuma et al, 1993). Fstl is a cardiokine whose levels are upregulated in models of acute and chronic injury, including MI, pressure overload-induced hypertrophy, and ischemia/reperfusion (I/R) injury (Oshima et al, 2008). Serum Fstl levels are significantly higher in patients with acute coronary syndrome (ACS) (Widera et al, 2009, 2012) and chronic systolic heart failure (El-Armouche et al, 2011)

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