Cardiac Myocyte-specific Ablation of Follistatin-like 3 Attenuates Stress-induced Myocardial Hypertrophy

Masayuki Shimano,Noriyuki Ouchi,Kazuto Nakamura,Yuichi Oshima,Akiko Higuchi,David R Pimentel,Kalyani D Panse,Enrique Lara-Pezzi,Se-Jin Lee,Flora Sam,Kenneth Walsh

doi:10.1074/jbc.m110.197079

Masayuki Shimano, Noriyuki Ouchi + Show 9 more

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https://doi.org/10.1074/jbc.m110.197079

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Abstract

Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 3 (Fstl3) is an extracellular regulator of certain TGF-β family members, including activin A. The aim of this study was to examine the role of Fstl3 in cardiac hypertrophy. Cardiac myocyte-specific Fstl3 knock-out (KO) mice and control mice were subjected to pressure overload induced by transverse aortic constriction (TAC). Cardiac hypertrophy was assessed by echocardiography and histological and biochemical methods. KO mice showed reduced cardiac hypertrophy, pulmonary congestion, concentric LV wall thickness, LV dilatation, and LV systolic dysfunction after TAC compared with control mice. KO mice displayed attenuated increases in cardiomyocyte cell surface area and interstitial fibrosis following pressure overload. Although activin A was similarly up-regulated in KO and control mice after TAC, a significant increase in Smad2 phosphorylation only occurred in KO mice. Knockdown of Fstl3 in cultured cardiomyocytes inhibited PE-induced cardiac hypertrophy. Conversely, adenovirus-mediated Fstl3 overexpression blocked the inhibitory action of activin A on hypertrophy and Smad2 activation. Transduction with Smad7, a negative regulator of Smad2 signaling, blocked the antihypertrophic actions of activin A stimulation or Fstl3 ablation. These findings identify Fstl3 as a stress-induced regulator of hypertrophy that controls myocyte size via regulation of Smad signaling.

Highlights

Cardiac hypertrophy is initially an adaptive response to preserve left ventricular (LV)3 function in response stresses, but sustained hypertrophic growth of the myocardium leads to an increased risk of cardiovascular events and death [1]
Cardiac Myocyte-specific Follistatinlike 3 (Fstl3) Deletion Attenuates Pressure Overload-induced Cardiac Hypertrophy and Dysfunction—To investigate the role of Fstl3 in cardiac hypertrophy, ␣-myosin heavy chain Creϩ/Ϫ;Fstl3flox/flox knock-out (KO) mice were used in which Fstl3 exons 3–5 are deleted in a cardiomyocytespecific manner
We and others have recently described that the expression of activin A and Fstl3 is induced in response to permanent left anterior descending artery ligation, myocardial ischemia-reperfusion injury, pressure-overload cardiac hypertrophy, and in end-stage heart failure patients, whereas the expression of other members of the activin/inhibin system, such as inhibin ␣ or Fst, is not affected [25, 26, 31]

Summary

Introduction

Cardiac hypertrophy is initially an adaptive response to preserve left ventricular (LV) function in response stresses, but sustained hypertrophic growth of the myocardium leads to an increased risk of cardiovascular events and death [1]. A better understanding of the processes that regulate cardiac hypertrophy could lead to the development of new treatments for heart failure [2]. To this end, a number of recent studies have sought to identify secreted proteins, referred to as cardiokines or cardiomyokines, that modulate cardiac hypertrophy via endocrine, paracrine, or autocrine mechanisms [3,4,5]. Follistatin (Fst) and follistatin-like (Fstl) proteins are extracellular regulators of TGF-␤ superfamily members [9] Both Fst and Fstl bind to and antagonize the action of activin A and myostatin [13, 14], but Fstl binds activin A with a much higher affinity than Fst through its N-terminal domain [15]. Role of Follistatin-like 3 in Cardiac Hypertrophy diac hypertrophy through a mechanism involving, at least in part, the inhibition of stress-induced activin A/Smad signaling

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