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

Abstract

Transforming growth factor-␤ family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatinlike 3 (Fstl3) is an extracellular regulator of certain TGF-␤ 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.

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

“…For example, follistatin-like 3 (Fstl3) binds to activin A and can modulate the heart's response to ischemic stress (7) and pressure overload (29). Although Fstl1 may function as an extracellular regulator of TGF-β family proteins in some scenarios, such as during development (30), we currently do not favor this hypothesis to account for Fstl1's antihypertrophic actions in the pressure-overloaded heart.…”

Biochemistry and Biology of GDF11 and Myostatin

“…FSTL3 is expressed in cardiac tissue 106 and its expression increases in end-stage failing myocardium in humans 107 . Heart mass, left ventricular and systolic pressure, and systolic arterial pressure are increased in FSTL3-deficient mice compared to wild-type mice 108 .…”

Structure of Myostatin·Follistatin-like 3

“…Fstl3 knock-out in mice is not lethal but leads to a variety of metabolic phenotypes (4). More recently, Fstl3 expression in cardiac myocytes has been shown to be necessary for the full development of cardiac hypertrophy (5). The severity of the effects of these Fst-type molecule deletions seems to inversely correlate with the specificity of the molecule deleted, because Fst is a more broad antagonist, whereas Fstl3 is narrower in scope and binds relatively fewer TGF-␤ family ligands (6).…”