Published online before print January 5, 2006, doi: 10.1161/01.RES.0000202804.84885.d0
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Submitted on March 4, 2005
Revised on December 15, 2005
Accepted on December 21, 2005
GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation
Jian Xu ;
From the Department of Pediatrics (J.X., R.K., T.E.H., J.D.M.), University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Ohio; Departments of Pharmacology (J.X.) and Physiology (J.N.L.), University of Cincinnati, Ohio; Department of Pediatrics (T.R.K.), Division of Cardiovascular Imaging, Children’s Hospital Medical Center, Cincinnati, Ohio; and Centre for Immunology (D.A.B., A.R.B., S.N.B.), St Vincent’s Hospital and University of New South Wales, Sidney, Australia.
* To whom correspondence should be addressed. E-mail: jeff.molkentin{at}cchmc.org.
Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-
superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene-targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.
Key words: cardiac • signaling • hypertrophy • growth factors • mouse genetics
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