Cardiac myocyte-specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy.
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.
Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, Massachusetts 02118, USA.
Masayuki
M
Shimano
Noriyuki
N
Ouchi
Kazuto
K
Nakamura
Yuichi
Y
Oshima
Akiko
A
Higuchi
David R
DR
Pimentel
Kalyani D
KD
Panse
Enrique
E
Lara-Pezzi
Se-Jin
SJ
Lee
Flora
F
Sam
Kenneth
K
Walsh
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D038702:Follistatin-Related Proteins; D055785:Gene Knockdown Techniques; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D038702:Follistatin-Related Proteins; C498620:Fstl3 protein, mouse; D011506:Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C497784:Smad2 protein, rat; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C497808:Smad7 protein, rat; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits
Cardiovasc Res. 2007 May 1;74(2):184-95
17109837
Science. 2002 May 31;296(5573):1646-7
12040180
Nature. 1997 Oct 9;389(6651):631-5
9335507
J Biol Chem. 2008 Nov 21;283(47):32831-8
18768470
Oncogene. 1998 Jun 4;16(22):2949-54
9671416
Circ Heart Fail. 2009 Nov;2(6):633-42
19919989
Circ Res. 2001 Aug 31;89(5):453-60
11532907
Circulation. 2004 Mar 23;109(11):1379-85
14993131
Mol Cell Endocrinol. 2004 Oct 15;225(1-2):25-8
15451564
Nat Med. 2004 Dec;10(12):1384-9
15558058
Exp Biol Med (Maywood). 2006 May;231(5):534-44
16636301
J Biol Chem. 2002 Oct 25;277(43):40735-41
12194980
Circ Res. 2005 Oct 14;97(8):821-8
16151019
Circulation. 2007 Oct 16;116(16):1768-75
17909105
Nature. 1997 May 1;387(6628):83-90
9139826
Annu Rev Physiol. 2001;63:391-426
11181961
J Clin Invest. 2005 Aug;115(8):2108-18
16075055
Circulation. 2009 Oct 20;120(16):1606-15
19805648
Endocrinology. 2001 Aug;142(8):3426-34
11459787
Endocrinology. 2008 Nov;149(11):5822-7
18617621
N Engl J Med. 1990 May 31;322(22):1561-6
2139921
J Cell Physiol. 2009 Aug;220(2):515-23
19415695
J Biol Chem. 2000 Dec 29;275(52):40788-96
11010968
Circulation. 2010 Jan 26;121(3):419-25
20065166
Endocrinology. 2006 Jul;147(7):3586-97
16627583
Cell. 2003 Jun 13;113(6):685-700
12809600
J Mol Cell Cardiol. 2006 Oct;41(4):689-97
16926021
Circ Res. 2006 Feb 17;98(3):342-50
16397142
J Card Fail. 2008 Oct;14(8):703-9
18926443
Exp Biol Med (Maywood). 2002 Oct;227(9):724-52
12324653
J Clin Invest. 1997 Jul 1;100(1):169-79
9202069
J Biol Chem. 2001 Aug 17;276(33):31133-41
11408477
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1348-53
17229845
Mol Cell Biol. 1996 Mar;16(3):1066-73
8622651
Circ Res. 2006 Jul 7;99(1):15-24
16763166
Mol Pharmacol. 2002 Jul;62(1):65-74
12065756